Wellcome to the PBPath Journal Watch!
This bi-monthly journal watch features exciting recently published pancreas and biliary pathology articles that will provide up to date medical knowledge in our field. These articles will be showcased in several convenient categories, including surgical pathology, cytopathology, and molecular pathology among others. The articles in each category are in no particular order. See the list of journals we search regularly here. Previous months’ issues may be found in our archive and you may see drafts of the upcoming issue here.
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We hope that you will enjoy the new PBPath Journal Watch!
- Akt1 signalling supports acinar proliferation and limits acinar-to-ductal metaplasia formation upon induction of acute pancreatitis
The Journal of pathology 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31531867
Molecular signalling mediated by the phosphatidylinositol-3-kinase (PI3K)-Akt axis is a key regulator of cellular functions. Importantly, alteration of the PI3K–Akt signalling underlies the development of different human diseases, thus prompting the investigation of the pathway as a molecular target for pharmacologic intervention. In this regard, recent studies showed that small molecule inhibitors of PI3K, the upstream regulator of the pathway, reduced the development of inflammation during acute pancreatitis, a highly debilitating and potentially lethal disease. Here we investigated whether a specific reduction of Akt activity, by using either pharmacologic Akt inhibition, or genetic inactivation of the Akt1 isoform selectively in pancreatic acinar cells, is effective in ameliorating the onset and progression of the disease. We discovered that systemic reduction of Akt activity did not protect the pancreas from initial damage and only transiently delayed leukocyte recruitment. However, reduction of Akt activity decreased acinar proliferation and exacerbated ADM formation, two critical events in the progression of pancreatitis. These phenotypes were recapitulated upon conditional inactivation of Akt1 in acinar cells, which resulted in reduced expression of 4E-BP1, a multifunctional protein of key importance in cell proliferation and metaplasia formation. Collectively, our results highlight the critical role played by Akt1 during the development of acute pancreatitis in the control of acinar cell proliferation and ADM formation. In addition, these results harbour important translational implications as they raise the concern that inhibitors of PI3K-Akt signalling pathways may negatively affect the regeneration of the pancreas. Finally, this work provides the basis for further investigating the potential of Akt1 activators to boost pancreatic regeneration following inflammatory insults. This article is protected by copyright. All rights reserved.
doi: https://doi.org/10.1002/path.5348
- Psychometric performance of the PAncreatic CAncer disease impact (PACADI) score
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31530448
BACKGROUND/OBJECTIVE: Pancreatic Cancer Disease Impact (PACADI) score measures the impact of pancreatic cancer (PC) on important health dimensions, selected by patients. The aim of this single center study was to test the psychometric performance of the Pancreatic Cancer Disease Impact (PACADI) score. METHODS: Patients with suspected pancreatic cancer (PC) completed PACADI, the EuroQol-5D (EQ-5D index) and Edmonton Symptom Assessment System (ESAS) in this longitudinal observational study. Measures were compared across patients with PC (n = 210), other malignant lesions (OML) (n = 109) and non-malignant lesions (NML) (n = 41). Associations, test-retest and internal consistency reliability, longitudinal changes, sensitivity to change and prediction of mortality during the first year were examined in patients with PC. RESULTS: The three measures discriminated between PC and OML. The PACADI score correlated strongly at baseline (n = 199)/after three months (n = 85) with the EQ-5D index and ESAS “sense of well-being” (0.64 and 0.66/0.73 and 0.69, p < 0.001, respectively), showed high test-retest reliability (ICC 0.84) and very good internal consistency reliability (Cronbach’s alpha 0.81-0.85) across all visits. Scores improved over time at 3, 6, 9 and 12 months for survivors, and standardized response mean (SRM) for improvement between 2 and 3 months (n = 44) was 0.80 (PACADI), -0.59 (EQ-5D index) and 0.69 (ESAS “sense of well-being”). The PACADI score significantly predicted mortality within the first year (p = 0.02) in contrast to the EQ-5D index and ESAS “sense of well-being”. CONCLUSION: This study showed satisfactory psychometric performance of the PACADI score. The results support its use in clinical practice and intervention trials.
doi: https://doi.org/10.1016/j.pan.2019.09.001
- Atp6ap2 deletion causes extensive vacuolation that consumes the insulin content of pancreatic β cells
Proceedings of the National Academy of Sciences of the United States of America 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31527264
Pancreatic β cells store insulin within secretory granules which undergo exocytosis upon elevation of blood glucose levels. Crinophagy and autophagy are instead responsible to deliver damaged or old granules to acidic lysosomes for intracellular degradation. However, excessive consumption of insulin granules can impair β cell function and cause diabetes. Atp6ap2 is an essential accessory component of the vacuolar ATPase required for lysosomal degradative functions and autophagy. Here, we show that Cre recombinase-mediated conditional deletion of Atp6ap2 in mouse β cells causes a dramatic accumulation of large, multigranular vacuoles in the cytoplasm, with reduction of insulin content and compromised glucose homeostasis. Loss of insulin stores and gigantic vacuoles were also observed in cultured insulinoma INS-1 cells upon CRISPR/Cas9-mediated removal of Atp6ap2. Remarkably, these phenotypic alterations could not be attributed to a deficiency in autophagy or acidification of lysosomes. Together, these data indicate that Atp6ap2 is critical for regulating the stored insulin pool and that a balanced regulation of granule turnover is key to maintaining β cell function and diabetes prevention.
doi: https://doi.org/10.1073/pnas.1903678116
- Bioactivation of napabucasin triggers reactive oxygen species-mediated cancer cell death
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31527169
PURPOSE: Napabucasin (2-acetylfuro-1,4-naphthoquinone or BBI-608) is a small molecule currently being clinically evaluated in various cancer types. It has mostly been recognized for its ability to inhibit STAT3 signaling. However, based on its chemical structure, we hypothesized that napabucasin is a substrate for intracellular oxidoreductases and therefore may exert its anti-cancer effect through redox cycling, resulting in reactive oxygen species (ROS) production and cell death. EXPERIMENTAL DESIGN: Binding of napabucasin to NAD(P)H:quinone oxidoreductase-1 (NQO1), and other oxidoreductases, was measured. Pancreatic cancer cell lines were treated with napabucasin, and cell survival, ROS generation, DNA damage, transcriptomic changes and alterations in STAT3 activation were assayed in vitro and in vivo. Genetic knock-out or pharmacological inhibition with dicoumarol was used to evaluate the dependency on NQO1. RESULTS: Napabucasin was found to bind with high affinity to NQO1 and to a lesser degree to cytochrome P450 oxidoreductase (POR). Treatment resulted in marked induction of ROS and DNA damage with an NQO1- and ROS-dependent decrease in STAT3 phosphorylation. Differential cytotoxic effects were observed, where NQO1-expressing cells generating cytotoxic levels of ROS at low napabucasin concentrations were more sensitive. Cells with low or no baseline NQO1 expression also produced ROS in response to napabucasin, albeit to a lesser extent, through the one-electron reductase POR. CONCLUSIONS: Napabucasin is bioactivated by NQO1, and to a lesser degree by POR, resulting in futile redox cycling and ROS generation. The increased ROS levels result in DNA damage and multiple intracellular changes, one of which is a reduction in STAT3 phosphorylation.
doi: https://doi.org/10.1158/1078-0432.CCR-19-0302
- Incidental pulmonary embolism in pancreatic ductal adenocarcinoma: Impact of tumor and AJCC stages at initial staging CT
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31522961
BACKGROUND/OBJECTIVES: To determine the prevalence of incidental pulmonary embolism (PE) detected during initial staging CT among patients with newly diagnosed pancreatic ductal adenocarcinoma (PDAC) and assess their association with underlying tumor burden. MATERIALS AND METHODS: This retrospective cohort study evaluated staging chest CT scans (2013-2017) to identify PE among patients with treatment naïve, biopsy-proven PDAC. Data included age, sex, T stage, AJCC stage, presence/absence of metastases and their location at diagnosis. The association of PE with tumor (T1-T4) and AJCC stage were assessed using Pearson Chi-square and Fischer’s exact test. A threshold p-value of <0.05 indicated statistical significance. RESULTS: A total of 174 patients (90 female, mean age, 68 years; range: 34-93) were identified, of which 10 patients harbored incidental PE (prevalence, 5.7%). In the PE group, two patients presented with distant metastasis (liver, 20%), while eight patients had T4 tumors (80%). No statistical association was detected between PE and age, sex, and the presence/absence or location of distant metastasis (p = 0.065, p = 0.59, p = 0.687 and p = 0.933, respectively). Patients with T4 tumors and higher AJCC stages (stage III/IV) were significantly more likely to present with PE than those with lower T stage (p = 0.045) and AJCC stage (stage I/II; p = 0.017). CONCLUSION: The prevalence of incidental PE among PDAC patients undergoing initial CT staging is 5.7%. Patients with T4 and AJCC stages III/IV are at higher risk of PE. Caution should be exercised during radiographic interpretation of initial staging chest CTs, as incidental PE may be lurking and require treatment.
doi: https://doi.org/10.1016/j.pan.2019.09.002
- A Semicentennial of Pancreatic Pathology: The Genetic Revolution Is Here, But Don’t Throw the Baby Out With The Bath Water!
Human pathology 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31521627
The last fifty years have witnessed an explosion in our understanding of the pathology of pancreatic diseases. Entities known to exist 50 years ago have been defined more precisely and are now better classified. New entities, previously not recognized, have been discovered and can now be treated. Importantly, new tools have been developed that have unraveled the fundamental biological drivers of a number of pancreatic diseases. Many of these same tools have also been applied clinically, supplementing the tried and true hematoxylin and eosin stained slide with a plethora of new, highly sensitive and specific tests that improve diagnostic accuracy and delineate best treatments. As exciting as these many advances are, our knowledge of pancreatic pathology remains incomplete, and there is much to be learned.
doi: https://doi.org/10.1016/j.humpath.2019.08.024
- Progress in cancer survival, mortality, and incidence in seven high-income countries 1995-2014 (ICBP SURVMARK-2): a population-based study
The Lancet. Oncology 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31521509
BACKGROUND: Population-based cancer survival estimates provide valuable insights into the effectiveness of cancer services and can reflect the prospects of cure. As part of the second phase of the International Cancer Benchmarking Partnership (ICBP), the Cancer Survival in High-Income Countries (SURVMARK-2) project aims to provide a comprehensive overview of cancer survival across seven high-income countries and a comparative assessment of corresponding incidence and mortality trends. METHODS: In this longitudinal, population-based study, we collected patient-level data on 3·9 million patients with cancer from population-based cancer registries in 21 jurisdictions in seven countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway, and the UK) for seven sites of cancer (oesophagus, stomach, colon, rectum, pancreas, lung, and ovary) diagnosed between 1995 and 2014, and followed up until Dec 31, 2015. We calculated age-standardised net survival at 1 year and 5 years after diagnosis by site, age group, and period of diagnosis. We mapped changes in incidence and mortality to changes in survival to assess progress in cancer control. FINDINGS: In 19 eligible jurisdictions, 3 764 543 cases of cancer were eligible for inclusion in the study. In the 19 included jurisdictions, over 1995-2014, 1-year and 5-year net survival increased in each country across almost all cancer types, with, for example, 5-year rectal cancer survival increasing more than 13 percentage points in Denmark, Ireland, and the UK. For 2010-14, survival was generally higher in Australia, Canada, and Norway than in New Zealand, Denmark, Ireland, and the UK. Over the study period, larger survival improvements were observed for patients younger than 75 years at diagnosis than those aged 75 years and older, and notably for cancers with a poor prognosis (ie, oesophagus, stomach, pancreas, and lung). Progress in cancer control (ie, increased survival, decreased mortality and incidence) over the study period was evident for stomach, colon, lung (in males), and ovarian cancer. INTERPRETATION: The joint evaluation of trends in incidence, mortality, and survival indicated progress in four of the seven studied cancers. Cancer survival continues to increase across high-income countries; however, international disparities persist. While truly valid comparisons require differences in registration practice, classification, and coding to be minimal, stage of disease at diagnosis, timely access to effective treatment, and the extent of comorbidity are likely the main determinants of patient outcomes. Future studies are needed to assess the impact of these factors to further our understanding of international disparities in cancer survival. FUNDING: Canadian Partnership Against Cancer; Cancer Council Victoria; Cancer Institute New South Wales; Cancer Research UK; Danish Cancer Society; National Cancer Registry Ireland; The Cancer Society of New Zealand; National Health Service England; Norwegian Cancer Society; Public Health Agency Northern Ireland, on behalf of the Northern Ireland Cancer Registry; The Scottish Government; Western Australia Department of Health; and Wales Cancer Network.
doi: https://doi.org/10.1016/S1470-2045(19)30456-5
- Lavage through percutaneous catheter drains in severe acute pancreatitis: Does it help?A randomized control trial
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31521496
AIMS: There is no study comparing large volume lavage through image guided percutaneously placed drains in severe acute pancreatitis. METHODS: Of the 114 randomized patients, 60 eligible candidates were randomly allocated to - Lavage Treatment (LT) group (28 patients) and Dependent Drainage (DD) group (32 patients). Primary end point was reversal of pre-existing organ failure, development of new onset organ failure, need for surgery, mortality and hospital stay. RESULTS: Both the groups were comparable in terms of demographic data, onset and severity of pancreatitis. LT group had higher infected pancreatic necrosis (75% vs 50%,p = 0.047). On intention to treat analysis, lavage treatment group showed a significant reversal of persistent organ failure (84% vs 50%, p = 0.23), reduction in APACHEII scores (3.5 ± 3.405 vs 1.16 ± 3.811 p = 0.012), as measured at the time of placement of PCD to cessation of intervention. There was no difference in development of new onset organ failure in the two groups (25% vs37.5% p=.290). 75% in LT group and 69% in DD group improved with PCD alone. There was no difference in the catheter related complications and number of catheters used. The need for surgical intervention was comparable in two groups (18.8% vs 14.3% p=.737). There was a trend toward decreased mortality in group A (18.8% vs 28.8% p=.370). CONCLUSION: Large volume lavage trough PCD improves organ failure and this translates into trend towards reduced mortality.
doi: https://doi.org/10.1016/j.pan.2019.09.003
- Preoperative chemotherapy and carbon ions therapy for treatment of resectable and borderline resectable pancreatic adenocarcinoma: a prospective, phase II, multicentre, single-arm study
BMC cancer 2019 Sep;19(1):922
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31521134
BACKGROUND: Pancreatic adenocarcinoma is a high-mortality neoplasm with a documented 5-years-overall survival around 5%. In the last decades, a real breakthrough in the treatment of the disease has not been achieved. Here we propose a prospective, phase II, multicentre, single-arm study aiming to assess the efficacy and the feasibility of a therapeutic protocol combining chemotherapy, carbon ion therapy and surgery for resectable and borderline resectable pancreatic adenocarcinoma. METHOD: The purpose of this trial (PIOPPO Protocol) is to assess the efficacy and the feasibility of 3 cycles of FOLFIRINOX neoadjuvant chemotherapy followed by a short-course of carbon ion radiotherapy (CIRT) for resectable or borderline resectable pancreatic adenocarcinoma patients. Primary outcome of this study is the assessment of local progression free survival (L-PFS). The calculation of sample size is based on the analysis of the primary endpoint “progression free survival” according to Fleming’s Procedure. DISCUSSION: Very preliminary results provide initial evidence of the feasibility of the combined chemotherapy and CIRT in the neoadjuvant setting for resectable or borderline resectable pancreatic cancer. Completion of the accrual and long term results are awaited to see if this combination of treatment is advisable and will provide the expected benefits. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03822936 registered on January 2019.
doi: https://doi.org/10.1186/s12885-019-6108-0
- Cancer biology as revealed by the research autopsy
Nature reviews. Cancer 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31519982
A research autopsy is a post-mortem medical procedure performed on a deceased individual with the primary goal of collecting tissue to support basic and translational research. This approach has increasingly been used to investigate the pathophysiological mechanisms of cancer evolution, metastasis and treatment resistance. In this Review, we discuss the rationale for the use of research autopsies in cancer research and provide an evidence-based discussion of the quality of post-mortem tissues compared with other types of biospecimens. We also discuss the advantages of using post-mortem tissues over other types of biospecimens, including the large amounts of tissue that can be obtained and the extent of multiregion sampling that is achievable, which is not otherwise possible in living patients. We highlight how the research autopsy has supported the identification of the clonal origins and modes of spread among metastases, the extent that selective pressures imposed by treatments cause bottlenecks leading to parallel and convergent tumour evolution, and the creation of rare tissue banks and patient-derived model systems. Finally, we comment on the future of the research autopsy as an integral component of precision medicine strategies.
doi: https://doi.org/10.1038/s41568-019-0199-4
- An Unusual Lung Mass of Heterotopic Pancreatic Tissue in a Neonate With an Elevated Immunoreactive Trypsinogen on Newborn Screen
Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 2019 Sep;():1093526619876820
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31514577
We present a case of a neonate with tracheoesophageal fistula and esophageal atresia along with a suspicious lung mass who had a false-positive newborn screen for cystic fibrosis due to an elevated serum immunoreactive trypsinogen with an additionally elevated serum lipase. The infant’s lung mass was found to contain heterotopic pancreatic tissue consisting of acini, ducts, and islet cells, without an associated gastrointestinal duplication cyst. This constellation of congenital abnormalities has not been described in previous literature. Also, this is the first reported case of a neonate with elevated serum pancreatic enzymes in which the underlying etiology was discovered to be heterotopic pancreas.
doi: https://doi.org/10.1177/1093526619876820
- Two cases of lung neuroendocrine carcinoma with carcinoid morphology
Diagnostic pathology 2019 Sep;14(1):104
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31511024
BACKGROUND: The category of grade 3 neuroendocrine tumor (NET G3) was newly introduced in the 2017 World Health Organization (WHO 2017) classification of neuroendocrine neoplasms of the pancreas. Pancreatic NET G3 shows a carcinoid-like morphology with high proliferative activity and the prognosis is intermediate between NET G2 and neuroendocrine carcinoma. There is no category corresponding to NET G3 in the current WHO 2015 classification of lung tumors. Herein, we report two cases of lung neuroendocrine carcinoma with carcinoid morphology that correspond to NET G3. CASE PRESENTATION: Case 1: An abnormal chest shadow was detected in a 78-year-old female never-smoker during a routine medical examination. She was asymptomatic. The radiological assessment revealed a mass in the peripheral S4 segment of the right lung. She underwent right middle lobectomy for the mass preoperatively diagnosed as non-small cell lung carcinoma. Postoperative histological examination revealed a neuroendocrine tumor with carcinoid morphology and a mitotic count of 15/2 mm2. Case 2: An abnormal chest shadow was detected in a 74-year-old female never-smoker undergoing follow-up for another disease. She was asymptomatic. The radiological assessment revealed a mass in the peripheral S3 segment of the right lung. She underwent right upper lobectomy for the mass suspected to be lung carcinoma. Postoperative histological examination revealed a neuroendocrine tumor with carcinoid morphology with mitotic count of 13/2 mm2. Both of these tumors showed carcinoid morphology but with a mitotic count exceeding 10/2 mm2; thus, we diagnosed them as small cell lung carcinomas according to the current WHO 2015 classification. CONCLUSIONS: Our tumors occurred in female never-smokers and their histology showed carcinoid morphology without extensive necrosis. Moreover, proliferative abilities of them were extremely low compared to small cell lung carcinoma. The clinical and pathological features of our tumors appeared to be different from those of small cell lung carcinoma. Although there is no category corresponding to NET G3 in the current classification of lung tumors, we consider that our tumors may correspond to NET G3 and identification of this subset is relevant for therapeutic management.
doi: https://doi.org/10.1186/s13000-019-0886-1
- Risk evaluation of splenic hilar or splenic artery lymph node metastasis and survival analysis for patients with proximal gastric cancer after curative gastrectomy: a retrospective study
BMC cancer 2019 Sep;19(1):905
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31510966
BACKGROUND: As splenectomy and spleen-preserving lymphadenectomy are performed only in some proximal gastric cancer patients, it is difficult to identify patients who have undergone radical gastrectomy with or without splenic hilar (No.10) or splenic artery (No.11) lymph node metastases. We aimed to determine the risk factors for No.10 and No.11 lymph node metastases and evaluate the survival significance of No.10 and No.11 lymph node dissection in advanced proximal gastric cancer patients. METHODS: A total of 873 advanced proximal gastric cancer patients who underwent curative gastrectomy with or without splenectomy or pancreaticosplenectomy were analyzed retrospectively. The clinicopathological characteristics of 152 patients who underwent splenectomy or pancreaticosplenectomy were analyzed to determine the risk factors for No.10 and No.11 lymph node metastases. The survival difference between patients with No.10 and No.11 lymph node dissections and those who did not undergo these dissections were compared. RESULTS: Patients with No.10 and No.11 lymph node metastases had very poor prognoses. Tumor invasion of the greater curvature and No.2 and No.4 lymph node metastases were independent risk factors for No.10 and No.11 lymph node metastases. No survival differences were evident between patients with No.10 and No.11 lymph node metastases who underwent No.10 and No.11 lymph node dissections and those who did not undergo these dissections but were at high risks of No.10 and No.11 lymph node metastases. CONCLUSIONS: Splenic hilar or splenic artery lymph node dissection was not associated with increased survival, in proximal gastric cancer patients without direct cancer invasion of the spleen and pancreas, regardless of whether splenectomy, pancreaticosplenectomy, or spleen-preserving lymphadenectomy was performed.
doi: https://doi.org/10.1186/s12885-019-6112-4
- Role of Ancillary Testing on Endoscopic US-Guided Fine Needle Aspiration Samples from Cystic Pancreatic Neoplasms
Acta cytologica 2019 Sep;64(1-2):1-12
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31509835
Pancreatic cysts are increasingly detected on imaging studies. Accurate determination of the cyst type is important to provide appropriate care for the patients. It is also very clear that not one single modality can provide adequate diagnostic information. A multidisciplinary approach is the key to the diagnosis of pancreatic cysts. In this setting, the role of ancillary testing, which includes biochemical testing (carcinoembryonic antigen and amylase levels in the cyst), molecular testing (e.g., KRAS, GNAS, VHL, and CTNB1), and/or immunohistochemical tests are very important to obtain an accurate diagnosis. This review will discuss helpful ancillary tests in common pancreatic cyst neoplasms and how to approach the diagnosis of pancreatic cysts.
doi: https://doi.org/10.1159/000502372
- A Clinicopathologic and Molecular Update of Pancreatic Neuroendocrine Neoplasms With a Focus on the New World Health Organization Classification
Archives of pathology & laboratory medicine 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31509453
CONTEXT.—: According to the 2017 World Health Organization classification, pancreatic neuroendocrine neoplasms (PanNENs) include a new category of pancreatic neuroendocrine tumor, grade 3, which is often difficult to differentiate from pancreatic neuroendocrine carcinoma. However, pancreatic neuroendocrine tumor grade 3 and pancreatic neuroendocrine carcinoma are distinct entities with very different clinical presentation, prognosis, and therapeutic strategies. Recent discoveries on the molecular characteristics of pancreatic neuroendocrine tumors also play an essential role in the pathologic differential diagnosis of PanNENs. In addition, the histopathologic varieties of PanNENs bring in many differential diagnoses with other pancreatic neoplasms, especially acinar cell carcinoma, solid pseudopapillary neoplasm, and ductal adenocarcinoma. OBJECTIVE.—: To provide a brief update of the World Health Organization classification; the clinical, histopathologic, immunohistochemical, and molecular characteristics; and the differential diagnoses and biological behavior of PanNENs. DATA SOURCES.—: Analysis of the pertinent literature (PubMed) and authors’ clinical practice experience based on institutional and consultation materials. CONCLUSIONS.—: The evolving clinical, histopathologic, immunohistochemical, and molecular features of PanNENs are reviewed. Important differential diagnoses with other neoplasms of the pancreas are discussed.
doi: https://doi.org/10.5858/arpa.2019-0338-RA
- Risk and subtypes of secondary primary malignancies in diffuse large B-cell lymphoma survivors change over time based on stage at diagnosis
Cancer 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31509235
BACKGROUND: Previous studies have shown an increased risk of secondary primary malignancies (SPMs) after diffuse large B-cell lymphoma (DLBCL) treatment. Whether stage of DLBCL at diagnosis affects the subtypes of SPMs that occur has not been previously described. METHODS: The Surveillance, Epidemiology, and End Results database was queried for patients aged >18 years diagnosed with primary DLBCL from 1973 to 2010 and categorized by early stage (ES) (stage I-II) or advanced stage (AS) (stage III-IV) disease. Differences in overall and location-specific SPM incidence by stage and time since diagnosis were assessed in 5-year intervals using a Fine-Gray hazards model. Overall survival was compared using the log-rank test. A Cox proportional hazards model was used to assess differences in survival. RESULTS: In total, 26,038 patients with DLBCL were identified, including 14,724 with ES and 11,314 with AS disease. The median follow-up was 13.3 years. Overall, 13.0% of patients developed SPM, with a higher but nonsignificantly increased risk of SPM development in those who had ES disease compared with those who had AS disease (14% vs 11.6%; P = .14). During the first 5 years after diagnosis, patients who had ES disease had a higher risk of SPM than those who had AS disease, specifically colorectal, pancreas, breast, and prostate SPMs. During the period from 10 to 15 years after diagnosis, patients who had AS disease had a higher risk of SPM than those who had ES disease, specifically hematologic SPMs. Development of SPM was found to significantly increase the risk of death regardless of stage at diagnosis. CONCLUSIONS: In this large, population-based study, distinctly different subtypes and temporal patterns of SPM development were identified based on stage of DLBCL at diagnosis. The current study merits consideration of tailored site-specific and time-specific surveillance for patients with DLBCL according to stage and time interval since diagnosis.
doi: https://doi.org/10.1002/cncr.32513
- Alcohol-dependent effect of PRSS1-PRSS2 haplotype in chronic pancreatitis
Gut 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31506327
doi: https://doi.org/10.1136/gutjnl-2019-319729
- Cytological appearance of pancreatic cystosis on fine-needle aspiration
Diagnostic cytopathology 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31503419
A 22-year-old Caucasian male with cystic fibrosis and recently diagnosed insulin-dependent diabetes mellitus underwent magnetic resonance imaging (MRI) and was found to have multiple cystic lesions in the pancreas. Endoscopic ultrasound evaluation revealed multiple macro- and microcystic components without mural nodules. One of the cysts in the body of the pancreas was in clear direct communication with the nondilated main pancreatic duct. Fine-needle aspiration (FNA) of two cysts was performed and showed foamy macrophages and rare ductal as well as acinar cells. Cell blocks showed nonpolarizable pink crystalloid material and small nonlaminated concretions consistent with inspissated secretions. Special stains for chymotrypsin and trypsin highlighted the acinar cells. Periodic acid Schiff, with and without diastase, was negative. Biopsy of the cyst wall showed ductal epithelial cells with underlying fibrotic stroma. This is the first description of the FNA appearance of pancreatic cystosis. We discuss the cytological differential diagnosis of cystic lesions of the pancreas and the biochemical as well as imaging findings used to arrive at the diagnosis.
doi: https://doi.org/10.1002/dc.24313
- Laparoscopic Distal Pancreatectomy for Left-Sided Pancreatic Cancer Using the “Caudo-Dorsal Artery First Approach”
Annals of surgical oncology 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31502021
BACKGROUND: Pancreatic cancer (PC) has serious malignant potential, thus requiring complete resection and adequate regional lymphadenectomy with tumor-free margins.1,2 A standard laparoscopic distal pancreatectomy (LDP) procedure for PC is not yet established due to lack of supportive evidence.3-6 METHODS: In our hospital, we first administered neoadjuvant chemoradiotherapy for resectable PC. Considering the benefits offered by a laparoscopic magnified caudo-dorsal view, we devised and standardized an LDP procedure for PC, which we employed in five patients with left-sided resectable tumors. First, the retroperitoneum was incised between the proximal jejunum and the inferior mesenteric vein with the transverse colon pushed up ventrally and cranially and with the proximal jejunum moved to the right. Then, the left renal vein (LRV) could be easily identified at this site. The retroperitoneal tissue was dissected along the LRV, and the origin of the superior mesenteric artery (SMA) also was identified just above the LRV easily. The left adrenal gland was removed to secure the dorsal margin, if needed. The retroperitoneal dissection was continued along the major anatomical landmarks, including the LRV, the left renal artery, the left kidney, and the crus of the diaphragm beside the origin of the SMA. Using the same operative field, lymphadenectomy around the SMA was performed before dividing the pancreas. We could safely and easily expose the left aspect of the SMA after dissecting the ligament of Treitz. The dissection around the SMA was performed toward the side of the arterial root that had already been exposed above the LRV. Thus, the most important difficult steps of LDP for PC, such as retroperitoneal dissection and lymphadenectomy around the SMA, were safely performed early in the operation with a good laparoscopic view. RESULTS: The median operative time was 341 (range 288-354) minutes, and median blood loss was 150 (range 50-150) ml. An intraoperative transfusion was not required for any patient. Severe postoperative complications or mortality were absent. An R0 resection was achieved in all patients. CONCLUSIONS: LDP using the “caudo-dorsal artery first approach” is safe and useful for performing a minimally invasive, curative resection for left-sided PC.
doi: https://doi.org/10.1245/s10434-019-07789-8
- Loss of ATRX expression predicts worse prognosis in pulmonary carcinoid tumors
Human pathology 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31499081
Loss of alpha thalassemia/mental retardation syndrome X-linked (ATRX), a chromatin regulator, is associated with worse prognosis in pancreatic neuroendocrine tumors. We investigated ATRX expression in pulmonary carcinoid tumors (PCT) and its diagnostic and prognostic role in these patients. Resected PCTs (1997-2017) were reviewed. Tumors were staged according to 8th UICC/AJCC system. ATRX nuclear expression was recorded independently by 2 reviewers. A cutoff of ≤5% of nuclear ATRX expression was statistically established as loss of expression. One-hundred-fifteen patients (72 women [63%]; median age of 60.5years [interquartile range, 50.8-71.5]) harbored 69 (60%) typical and 46 (40%) atypical PCTs. Median tumor size was 2.3cm (interquartile range, 1.6-3.8cm). Loss of ATRX expression was associated with atypical PCTs (OR 7.4 [95% CI: 2.6-23, P<.001]), when adjusted for lymphovascular invasion and perineural invasion. ATRX expression predicted atypical PCT with sensitivity of 37% (95% CI: 24-52%), specificity of 92% (95% CI: 86-98%), AUC of 0.62 (95% CI: 0.52-0.72). Loss of ATRX expression was associated with shorter disease-specific survival (HR=11, 95% CI 1.8-68, P=.01), after adjusting for lymphovascular invasion and presence of metastatic disease at time of diagnosis. Interobserver agreement on ATRX expression by two reviewers was substantial (κ=0.72 [95% CI: 0.60-0.80]). ATRX expression is more commonly lost in atypical than in typical PCT, and is associated with more aggressive tumor characteristics and shorter disease-specific survival.
doi: https://doi.org/10.1016/j.humpath.2019.08.022
- Does the Artery-first Approach Improve the Rate of R0 Resection in Pancreatoduodenectomy?: A Multicenter, Randomized, Controlled Trial
Annals of surgery 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31498183
OBJECTIVE: To compare the rates of R0 resection in pancreatoduodenectomy (PD) for pancreatic and periampullary malignant tumors by means of standard (ST-PD) versus artery-first approach (AFA-PD). BACKGROUND: Standardized histological examination of PD specimens has shown that most pancreatic resections thought to be R0 resections are R1. “Artery-first approach” is a surgical technique characterized by meticulous dissection of arterial planes and clearing of retropancreatic tissue in an attempt to achieve a higher rate of R0. To date, studies comparing AFA-PD versus ST-PD are retrospective cohort or case-control studies. METHODS: A multicenter, randomized, controlled trial was conducted in 10 University Hospitals (NCT02803814, ClinicalTrials.gov). Eligible patients were those who presented with pancreatic head adenocarcinoma and periampullary tumors (ampulloma, distal cholangiocarcinoma, duodenal adenocarcinoma). Assignment to each group (ST-PD or AFA-PD) was randomized by blocks and stratified by centers. The primary end-point was the rate of tumor-free resection margins (R0); secondary end-points were postoperative complications and mortality. RESULTS: One hundred seventy-nine patients were assessed for eligibility and 176 randomized. After exclusions, the final analysis included 75 ST-PD and 78 AFA-PD. R0 resection rates were 77.3% (95% CI: 68.4-87.4) with ST-PD and 67.9% (95% CI: 58.3-79.1) with AFA-PD, P=0.194. There were no significant differences in postoperative complication rates, overall 73.3% versus 67.9%, and perioperative mortality 4% versus 6.4%. CONCLUSIONS: Despite theoretical oncological advantages associated with AFA-PD and evidence coming from low-level studies, this multicenter, randomized, controlled trial has found no difference neither in R0 resection rates nor in postoperative complications in patients undergoing ST-PD versus AFA-PD for pancreatic head adenocarcinoma and other periampullary tumors.
doi: https://doi.org/10.1097/SLA.0000000000003535
- Risk analysis of extended pancreas donor selection criteria
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31495709
INTRODUCTION: The success of pancreas transplantation, in combination with a stable number of available allografts has resulted in an increasing waiting list. This study investigated donor potential by expanding age and Body Mass Index (BMI) criteria. METHODS: All reported donors in the Netherlands between 2013 and 2017 were analysed. Risk assessment of extended criteria donors was done by in-depth analysis of donor reports and calculation of the Pancreas Donor Risk Index (PDRI). The PDRI of these extended criteria donors was compared to standard criteria donors to evaluate the increased risk on graft failure. RESULTS: A total of 1273 donors were reported. Of these donors, 405 donors were reported as pancreas donor, of which 93 (23%) pancreata were transplanted. Extending age criterion with 5 years could result in additional 40 Donation after Brain Death donors and 37 Donation after Circulatory Death donors reported. In 24 (31%) extended age criteria donors the PDRI was below the upper limit of currently transplanted pancreata. Extending BMI criteria to 35 kg/m2 could result in an additional 19 (6%) donors reported. CONCLUSIONS: Extending BMI criteria could result in a slight increase of reported donors. Extending age criteria increased significantly the number of reported donors. In 24 (31%) of the older donors the PDRI showed a reduced risk compared to currently transplanted pancreata. This study suggest that, if other risk factors are absent, pancreata of extended age and/or BMI criteria donors should be considered for transplantation.
doi: https://doi.org/10.1016/j.pan.2019.08.010
- Ca2+ Influx Channel Inhibitor SARAF Protects Mice From Acute Pancreatitis
Gastroenterology 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31493399
BACKGROUND & AIMS: Pancreatitis is characterized by increased influx of Ca2+ into acinar cells, by unknown mechanisms. Inhibitors of Ca2+ influx channels could be effective in treating acute pancreatitis, but these have deleterious side effects that can result in death. We investigated the expression patterns and functions of acinar cell Ca2+ channels and factors that regulate them during development of acute pancreatitis, along with changes in the channel inactivator store-operated calcium entry associated regulatory factor (SARAF). We investigated whether SARAF is a target for treatment of acute pancreatitis and its status in human with pancreatitis. METHODS: We generated mice that expressed SARAF tagged with hemagglutinin, using CRISPR/Cas9 gene editing, and isolated acinar cells. We also performed studies with Saraf-/- mice, Sarafzf/zf mice, mice without disruption of Saraf (control mice), and mice that overexpress fluorescently labeled SARAF in acinar cells. We analyzed interactions between stromal interaction molecule 1 (STIM1) and SARAF in HEK cells stimulated with carbachol using fluorescence resonance energy transfer microscopy and immunoprecipitation. Mice were given injections of caerulein or L-arginine to induce pancreatitis. Pancreatic tissues and blood samples were collected and levels of serum amylase, trypsin, tissue damage, inflammatory mediators, and inflammatory cells were measured. We performed quantitative PCR analyses of pancreatic tissues from 6 organ donors without pancreatic disease (controls) and 9 patients with alcohol-associated pancreatitis. RESULTS: Pancreatic levels of Ca2+ influx channels or STIM1 did not differ significantly between acinar cells from mice with vs without pancreatitis. By contrast, pancreatic levels of Saraf mRNA and SARAF protein initially markedly increased but then decreased during cell stimulation or injection of mice with caerulein, resulting in excessive Ca2+ influx. STIM1 interacted stably with SARAF following stimulation of HEK or mouse acinar cells with physiologic levels of carbachol, but only transiently following stimulation with pathologic levels of carbachol, leading to excessive Ca2+ influx. We observed reduced levels of SARAF mRNA in pancreatic tissues from patients with pancreatitis, compared with controls. SARAF-knockout mice developed more severe pancreatitis than control mice after administration of caerulein or L-arginine, and pancreatic acinar cells from these mice had significant increases in Ca2+ influx. Conversely, overexpression of SARAF in acini reduced Ca2+ influx, eliminated inflammation and reduced severity of acute pancreatitis. CONCLUSIONS: In mice with pancreatitis, SARAF initially increases but is then degraded, resulting in excessive, pathological Ca2+ influx by acinar cells. SARAF-knockout mice develop more severe pancreatitis than control mice, whereas mice that express SARAF from a transgene in acinar cells develop less-severe pancreatitis. SARAF therefore appears to prevent pancreatic damage during development of acute pancreatitis. Strategies to stabilize or restore SARAF to acinar cells might be developed for treatment of pancreatitis.
doi: https://doi.org/10.1053/j.gastro.2019.08.042
- Goals of Treatment Sequencing for Localized Pancreatic Cancer
Annals of surgical oncology 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31493126
doi: https://doi.org/10.1245/s10434-019-07738-5
- Identification of Resistance Pathways Specific to Malignancy Using Organoid Models of Pancreatic Cancer
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31492749
PURPOSE: KRAS is mutated in the majority of pancreatic ductal adenocarcinoma. MAPK and PI3K-AKT are primary KRAS effector pathways, but combined MAPK and PI3K inhibition has not been demonstrated to be clinically effective to date. We explore the resistance mechanisms uniquely employed by malignant cells. EXPERIMENTAL DESIGN: We evaluated the expression and activation of receptor tyrosine kinases in response to combined MEK and AKT inhibition in KPC mice and pancreatic ductal organoids. Additionally, we sought to determine the therapeutic efficacy of targeting resistance pathways induced by MEK and AKT inhibition in order to identify malignant-specific vulnerabilities. RESULTS: Combined MEK and AKT inhibition modestly extended the survival of KPC mice and increased Egfr and ErbB2 phosphorylation levels. Tumor organoids, but not their normal counterparts, exhibited elevated phosphorylation of ERBB2 and ERBB3 after MEK and AKT blockade. A pan-ERBB inhibitor synergized with MEK and AKT blockade in human PDA organoids, whereas this was not observed for the EGFR inhibitor Erlotinib. Combined MEK and ERBB inhibitor treatment of human organoid orthotopic xenografts was sufficient to cause tumor regression in short-term intervention studies. CONCLUSIONS: Analyses of normal and tumor pancreatic organoids revealed the importance of ERBB activation during MEK and AKT blockade primarily in the malignant cultures. The lack of ERBB hyperactivation in normal organoids suggests a larger therapeutic index. In our models pan-ERBB inhibition was synergistic with dual inhibition of MEK and AKT and the combination of a pan-ERBB inhibitor with MEK antagonists showed the highest activity both in vitro and in vivo.
doi: https://doi.org/10.1158/1078-0432.CCR-19-1398
- MiR-194-5p in Pancreatic Ductal Adenocarcinoma Peritoneal Washings is Associated with Peritoneal Recurrence and Overall Survival in Peritoneal Cytology-Negative Patients
Annals of surgical oncology 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31489551
BACKGROUND: Peritoneal dissemination is one of the major recurrence patterns in patients with pancreatic ductal adenocarcinoma (PDAC) and is associated with poor prognosis. Here, we assessed the diagnostic potential of microRNA (miRNA) profiles in peritoneal washings for prediction of peritoneal dissemination in PDAC. PATIENTS AND METHODS: From January 2016 to July 2017, peritoneal washings were obtained prospectively from 59 patients with PDAC undergoing surgery the Yokohama City University Hospital. MiRNA expression was evaluated by Agilent human miRNA microarray and quantitative reverse-transcription polymerase chain reaction. RESULTS: Microarray analysis identified upregulated and downregulated miRNAs in peritoneal washings of patients with peritoneal dissemination. We validated four miRNAs (miR-141-3p, miR-194-3p, miR-194-5p, and miR-200c-3p) with high expression in peritoneal washings. The cumulative incidence rate of peritoneal recurrence in peritoneal cytology-negative patients in the miR-194-5p high group was significantly higher than that in the miR-194-5p low group (p = 0.002). Univariate and multivariate analyses revealed that high miR-194-5p was associated with overall survival (OS). CONCLUSIONS: High expression of miR-194-5p in peritoneal washings is associated with peritoneal recurrence and poor OS in patients with peritoneal cytology-negative PDAC.
doi: https://doi.org/10.1245/s10434-019-07793-y
- Localized malignant mesothelioma, an unusual and poorly characterized neoplasm of serosal origin: best current evidence from the literature and the International Mesothelioma Panel
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31485011
Localized malignant mesotheliomas (LMM) is an uncommon and poorly recognized neoplasm. Its pathologic diagnosis is often surprising in patients with serosal/subserosal based localized tumors that are clinically suspicious for metastatic lesions or primary sarcomas. Once a tumor is diagnosed as “mesothelioma”, LMM is often mistaken for diffuse malignant mesothelioma (DMM). Best currently available evidence about LMM was collected from the literature and cases diagnosed by members of the International Mesothelioma Panel (IMP). One hundred and one (101) LMM have been reported in the English literature. Patients had localized tumors with identical histopathologic features to DMM. Patients ranged in age from 6 to 82 years; 75% were men. Most (82%) of the tumors were intrathoracic. Others presented as intrahepatic, mesenteric, gastric, pancreatic, umbilical, splenic, and abdominal wall lesions. Tumors varied in size from 0.6 to 15 cm. Most patients underwent surgical resection and/or chemotherapy or radiation therapy. Median survival in a subset of patients was 29 months. Seventy two additional LMM from IMP institutions ranged in age from 28 to 95 years; 58.3% were men. Sixty tumors (83.3%) were intrathoracic, others presented in intraabdominal sites. Tumors varied in size from 1.2 to 19 cm. Median survival for 51 cases was 134 months. Best evidence was used to formulate guidelines for the diagnosis of LMM. It is important to distinguish LMM from DMM as their treatment and prognosis is different. A multidisciplinary approach is needed for the diagnosis of LMM as it shows identical histopathology and immunophenotype to DMM.
doi: https://doi.org/10.1038/s41379-019-0352-3
- Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells
Proceedings of the National Academy of Sciences of the United States of America 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31484774
Pancreatic ductal adenocarcinoma (PDAC) has prominent extracellular matrix (ECM) that compromises treatments yet cannot be nonselectively disrupted without adverse consequences. ECM of PDAC, despite the recognition of its importance, has not been comprehensively studied in patients. In this study, we used quantitative mass spectrometry (MS)-based proteomics to characterize ECM proteins in normal pancreas and pancreatic intraepithelial neoplasia (PanIN)- and PDAC-bearing pancreas from both human patients and mouse genetic models, as well as chronic pancreatitis patient samples. We describe detailed changes in both abundance and complexity of matrisome proteins in the course of PDAC progression. We reveal an early up-regulated group of matrisome proteins in PanIN, which are further up-regulated in PDAC, and we uncover notable similarities in matrix changes between pancreatitis and PDAC. We further assigned cellular origins to matrisome proteins by performing MS on multiple lines of human-to-mouse xenograft tumors. We found that, although stromal cells produce over 90% of the ECM mass, elevated levels of ECM proteins derived from the tumor cells, but not those produced exclusively by stromal cells, tend to correlate with poor patient survival. Furthermore, distinct pathways were implicated in regulating expression of matrisome proteins in cancer cells and stromal cells. We suggest that, rather than global suppression of ECM production, more precise ECM manipulations, such as targeting tumor-promoting ECM proteins and their regulators in cancer cells, could be more effective therapeutically.
doi: https://doi.org/10.1073/pnas.1908626116
- Altered gene expression along the glycolysis-cholesterol synthesis axis is associated with outcome in pancreatic cancer
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31481506
PURPOSE: Identification of clinically actionable molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcome. Inter-tumoral metabolic heterogeneity contributes to cancer survival and the balance between distinct metabolic pathways may influence PDAC outcome. We hypothesized that PDAC can be stratified into prognostic metabolic subgroups based on alterations in the expression of genes involved in glycolysis and cholesterol synthesis. EXPERIMENTAL DESIGN: We performed bioinformatics analysis of genomic, transcriptomic and clinical data in an integrated cohort of 325 resectable and non-resectable PDAC. The resectable datasets included retrospective The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) cohorts. The non-resectable PDAC cohort studies included prospective COMPASS, PanGen and BC Cancer Personalized OncoGenomics program (POG). RESULTS: Based on the median normalized expression of glycolytic and cholesterogenic genes, four subgroups were identified: quiescent, glycolytic, cholesterogenic and mixed. Glycolytic tumors were associated with the shortest median survival in resectable (log-rank test P=0.018) and metastatic settings (log-rank test P=0.027). Patients with cholesterogenic tumors had the longest median survival. KRAS and MYC amplified tumors had higher expression of glycolytic genes than tumors with normal or lost copies of the oncogenes (Wilcoxon rank sum test P=0.015). Glycolytic tumors had the lowest expression of mitochondrial pyruvate carriers MPC1 and MPC2 Glycolytic and cholesterogenic gene expression correlated with the expression of prognostic PDAC subtype classifier genes. CONCLUSIONS: Metabolic classification specific to glycolytic and cholesterogenic pathways provides novel biological insight into previously established PDAC subtypes and may help develop personalized therapies targeting unique tumor metabolic profiles.
doi: https://doi.org/10.1158/1078-0432.CCR-19-1543
- American Gastroenterological Association Clinical Practice Update: Management of Pancreatic Necrosis
Gastroenterology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31479658
DESCRIPTION: The purpose of this AGA Institute Clinical Practice Update is to review the available evidence and expert recommendations regarding the clinical care of patients with pancreatic necrosis and to offer concise best practice advice for the optimal management of patients with this highly morbid condition. METHODS: This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPUC and external peer review through standard procedures of Gastroenterology. This review is framed around the 15 best practice advice points agreed upon by the authors, which reflect landmark and recent published manuscripts in this field. This expert review also reflects the experiences of the authors who are advanced endoscopists or hepatopancreatobiliary surgeons with extensive experience in managing and teaching others to care for patients with pancreatic necrosis.
doi: https://doi.org/10.1053/j.gastro.2019.07.064
- Comment on “Deleterious Effect of RAS and Evolutionary High-risk TP53 Double Mutation in Colorectal Liver Metastases”
Annals of surgery 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31478983
doi: https://doi.org/10.1097/SLA.0000000000003600
- Comparison of the clinicopathological features of pancreatic solid pseudopapillary neoplasms between males and females: gender does matter
Histology and histopathology 2019 Sep;():18156
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31478554
BACKGROUND: Solid pseudopapillary neoplasms (SPN) of the pancreas are a rare and low-grade malignant entity with a female predominance. However, it also occurs in males, but the rarity and lack of concern makes its clinicopathological features unclarified. METHODS: The morphological, immunohistochemical, prognostic features and CTNNB1 exon 3 mutation status of SPN were compared semi-quantitively between 9 male and 21 female patients. RESULTS: SPN in males grew in a distinctive solid pattern, with abundant fibrotic stroma and clear cells. Collagen tended to be the main component of tumor stroma in males, while hyaluronan composed a considerable proportion in females. A much stronger expression of androgen receptor (AR) was found in males, and CD56 and/or synaptophysin (Syn) was expressed frequently in both genders. All patients survived. One male patient had post-operational liver nodules and accepted interventional therapy without biopsy. Mutations of CTNNB1 exon 3 were observed in all cases, distributed at codon 32, 33 and 37 in both genders, as well as 34, 41 and 62 in females. CONCLUSION: SPN in males presented with significantly different morphological features from that in females, which might be helpful in differential diagnosis, especially when with extensive positivity for CD56 and/or Syn. The stronger expression of AR in males might be a clue to explore the underlying mechanism of the gender difference.
doi: https://doi.org/10.14670/HH-18-156
- Serotonin and Dopamine Receptor Expression in Solid Tumours Including Rare Cancers
Pathology oncology research : POR 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31478179
In preclinical studies serotonin stimulates and dopamine inhibits tumour growth and angiogenesis. Information regarding serotonin and dopamine receptor (5-HTR and DRD) expression in human cancers is limited. Therefore, we screened a large tumour set for receptor mRNA overexpression using functional genomic mRNA (FGmRNA) profiling, and we analysed protein expression and location of 5-HTR1B, 5-HTR2B, DRD1, and DRD2 with immunohistochemistry in different tumour types. With FGmRNA profiling 11,756 samples representing 43 tumour types were compared to 3,520 normal tissue samples to analyse receptor overexpression. 5-HTR2B overexpression was present in many tumour types, most frequently in uveal melanomas (56%). Receptor overexpression in rare cancers included 5-HTR1B in nasopharyngeal carcinoma (17%), DRD1 in ependymoma (30%) and synovial sarcoma (21%), and DRD2 in astrocytoma (13%). Immunohistochemistry demonstrated high 5-HTR2B protein expression on melanoma and gastro-intestinal stromal tumour cells and endothelial cells of colon, ovarian, breast, renal and pancreatic tumours. 5-HTR1B expression was predominantly low. High DRD2 protein expression on tumour cells was observed in 48% of pheochromocytomas, and DRD1 expression ranged from 14% in melanoma to 57% in renal cell carcinoma. In conclusion, 5-HTR1B, 5-HTR2B, DRD1, and DRD2 show mRNA overexpression in a broad spectrum of common and rare cancers. 5-HTR2B protein is frequently highly expressed in human cancers, especially on endothelial cells. These findings support further investigation of especially 5HTR2B as a potential treatment target.
doi: https://doi.org/10.1007/s12253-019-00734-w
- Long-term Risk of Malignancy in Branch Duct Intraductal Papillary Mucinous Neoplasms
Gastroenterology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31473224
BACKGROUND & AIMS: Long-term outcomes of patients with branch-duct intraductal papillary mucinous neoplasms (IPMNs), particularly those after 5 years if surveillance, have not been fully evaluated in large studies. We analyzed incidences of IPMN-derived carcinoma and concomitant ductal adenocarcinoma (PDAC) over 20 years in a large population of patients. METHODS: We identified 1404 consecutive patients (52% female; mean age, 67.5 years) with a diagnosis of branch-duct IPMN, from 1994 through 2017, at the University of Tokyo in Japan. Using a competing-risk analysis, we estimated cumulative incidence of pancreatic carcinoma, overall and by carcinoma type. We used competing-risks proportional hazards models to estimate sub-distribution hazard ratios (SHRs) for incidences of carcinomas. To differentiate IPMN-derived and concomitant carcinomas, we collected genomic DNA from available paired samples of IPMNs and carcinomas and detected mutations in GNAS and KRAS by PCR and pyrosequencing. RESULTS: During 9231 person-years of follow up, we identified 68 patients with pancreatic carcinomas (38 patients with IPMN-derived carcinomas and 30 patients with concomitant PDACs); the overall incidence rates were 3.3%, 6.6%, and 15% at 5, 10, and 15 years, respectively. Among 804 patients followed more than 5 years, overall cumulative incidence rates of pancreatic carcinoma were 3.5% at 10 years and 12% at 15 years from the initial diagnosis. The size of the IPMN and the diameter of the main pancreatic duct associated with incidence of IPMN-derived carcinoma (SHR, 1.85; 95% CI, 1.38-2.48 for a 10-mm increase in the IPMN size and SHR, 1.56; 95% CI, 1.33-1.83 for a 1-mm increase in the main pancreatic duct diameter) but not with incidence of concomitant PDAC CONCLUSIONS: In a large long-term study of patients with branch-duct IPMNs, we found the 5-year incidence rate of pancreatic malignancy to be 3.3%, reaching 15% at 15 years after IPMN diagnosis. We observed heterogeneous risk factor profiles between IPMN-derived and concomitant carcinomas.
doi: https://doi.org/10.1053/j.gastro.2019.08.032
- Modulation of all-trans retinoic acid-induced MiRNA expression in neoplastic cell lines: a systematic review
BMC cancer 2019 Aug;19(1):866
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31470825
BACKGROUND: Cancer is a genetic and epigenetic disease that involves inactivation of tumor suppressor genes and activation of proto-oncogenes. All-trans retinoic acid (ATRA) is an isomer of retinoic acid involved in the onset of differentiation and apoptosis of a number of normal and cancer cells, functioning as an anti-cancer agent in several neoplasms. Ectopic changes in the expression of certain microRNAs (miRNAs) occur in response to ATRA, leading to phenotypic alterations in neoplastic cell lines. Moreover, the modulation of miRNA patterns upon ATRA-treatment may represent an effective chemopreventive and anti-cancer therapy strategy. The present systematic review was performed to provide an overview of the modulation of ATRA-induced miRNA expression in different types of neoplastic cells and identify the efficacy of intervention factors (i.e., concentration and duration of treatment) and how they influence expression profiles of oncogenesis-targeting miRNAs. METHODS: A systematic search was conducted according to the PRISMA statement via the US National Library of Medicine MEDLINE/PubMed bibliographic search engine. RESULTS: The search identified 31 experimental studies involving human cell lines from nine different cancer types (neuroblastoma, acute myeloid leukemia, breast cancer, lung cancer, pancreatic cancer, glioma, glioblastoma, embryonal carcinoma, and colorectal cancer) treated with ATRA at concentrations ranging from 10- 3 μmol/L to 102 μmol mol/L for 24 h to 21 days. CONCLUSION: The concentrations used and the duration of treatment of cancer cells with ATRA varied widely. The presence of ATRA in the culture medium of cancer cells was able to modulate the expression of more than 300 miRNAs, and inhibit invasive behavior and deregulated growth of cancer cells, resulting in total tumor remission in some cases. ATRA may thus be broadly effective for neoplasm treatment and prevention, although these studies may not accurately represent in vivo conditions. Additional studies are required to elucidate ATRA-induced miRNA modulation during neoplasm treatment.
doi: https://doi.org/10.1186/s12885-019-6081-7
- CA19-9 decrease and survival according to platelet level in patients with advanced pancreatic cancer
BMC cancer 2019 Aug;19(1):860
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31470818
BACKGROUND: CA19-9 decrease during treatment has been associated with superior survival of pancreatic cancer in several studies. The evidence to show the correlation of high platelet level with inferior survival is insufficient in pancreatic cancer. It also remains unclear whether the association between CA19-9 decrease and survival was corresponded to different levels of platelet in metastatic pancreatic cancer. METHODS: We measured CA19-9 serum concentration and platelet level at baseline and after the second cycle of chemotherapy for 200 advanced pancreatic cancer patients. A Cox proportional hazards model was used to compute mortality hazard ratios (HRs) for CA19-9 decrease, adjusting for potential confounders, including age, sex, KPS, prediagnosis body mass index, Diabetes Mellitus, tumor location, first-line chemotherapy regimen, and radiotherapy. RESULTS: We found that the association of CA19-9 decrease with superior overall survival was stronger in advanced pancreatic cancer with a low level of platelet (Pinteraction < 0.001) compared with intermediate and high level of platelet. Multivariable-adjusted hazard ratios per unit decrease of CA19-9 change was 0.45 [95% confidence interval (CI), 0.33 to 0.62] in cases with low platelet level, 0.74 (95% CI, 0.50 to 1.09) in cases with intermediate platelet level, and 0.94 (95% CI, 0.74 to 1.10) in cases with high platelet level. A similar differential association was found between CA19-9 decrease and progression-free survival in strata of platelet level (Pinteraction = 0.034). CONCLUSION: The association of CA19-9 decrease with superior pancreatic cancer survival appeared to be pronounced in patients with a low platelet level. This finding could provide supports for the underlying mechanisms of CA19-9 involved in platelet / tumor cell interaction.
doi: https://doi.org/10.1186/s12885-019-6078-2
- Higher IL-6 peri-tumoural expression is associated with gastro-intestinal neuroendocrine tumour progression
Pathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31466863
An association of well-differentiated gastroenteropancreatic neuroendocrine tumours (WD GEP NETs) with metabolic syndrome (MetS) was recently described. Yet no molecular mechanisms linking the two conditions are known. This study’s aim was to identify putative molecular signatures linking WD GEP NETs and MetS to gain further insight into potential mechanisms for this association. Patients with WD GEP NETs (n=39), pancreatic (panNET) and gastro-intestinal (GI-NET), were clinically evaluated for presence of MetS. WD GEP NETs immunohistochemistry staining for Forkhead box protein M1 (FOXM1), insulin growth factor 1 receptor (IGF1R), Ki-67 and interleukin 6 (IL-6) was performed and quantified by computerised morphometric analysis. FOXM1, Ki-67, IGF1R or IL-6 expression in WD GEP NETs was not influenced by the presence of MetS. IL-6 peritumoural expression was higher in GI-NETs of patients with low HDL cholesterol (0.018±0.005% vs 0.030±0.005%, p=0.02). In GI-NETs, a higher IL-6 expression was also associated with disease progression (0.026±0.004% vs 0.016±0.002%, p=0.03). In WD GEP-NETs, MetS did not influence FOXM1, IGF1R and IL-6 expression. In GI-NETs, IL-6 expression was influenced by the MetS feature low HDL, and positively associated with disease progression. These data suggest that local and systemic inflammatory status can potentially modulate GI-NET behaviour.
doi: https://doi.org/10.1016/j.pathol.2019.07.001
- The differential distributions of ASPM isoforms and their roles in Wnt signaling, cell cycle progression, and pancreatic cancer prognosis
The Journal of pathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31465125
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and treatment-resistant malignancy. The lack of pathway-informed biomarkers hampers the development of rational diagnostics or therapies. Recently, the protein abnormal spindle-like microcephaly associated (ASPM) was identified as a novel Wnt and stemness regulator in PDAC, while the pathogenic roles of its protein isoforms remain unclarified. We developed novel isoform-specific antibodies and genetic knockdown (KD) of putative ASPM isoforms, whereby we uncovered that the levels of ASPM isoform 1 (iI) and ASPM-iII are variably up-regulated in PDAC cells. ASPM isoforms show remarkably different subcellular locations; specifically, ASPM-iI is exclusively localized to the cortical cytoplasm of PDAC cells while ASPM-iII is predominantly expressed in cell nuclei. Mechanistically, ASPM-iI colocalizes with disheveled-2 and active β-catenin as well as the stemness marker aldehyde dehydrogenase-1 (ALDH-1), and its expression is indispensable for the Wnt activity, stemness and the tumorigenicity of PDAC cells. By contrast, ASPM-iII selectively regulates the expression level of cyclin E and cell cycle progression in PDAC cells. The expression of ASPM-iI and ASPM-iII display considerable intratumoral heterogeneity in PDAC tissues and only that of ASPM-iI was prognostically significant; it outperformed ALDH-1 staining and clinico-pathological variables in a multivariant analysis. Collectively, the distinct expression patterns and biological functions of ASPM isoforms may illuminate novel molecular mechanisms and prognosticators in PDAC and may pave the road for the development of therapies targeting this novel oncoprotein. This article is protected by copyright. All rights reserved.
doi: https://doi.org/10.1002/path.5341
- Chronic inflammation markers are associated with risk of pancreatic cancer in the Swedish AMORIS cohort study
BMC cancer 2019 Aug;19(1):858
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31464604
BACKGROUND: Nested case-control studies examining the association between serum markers of chronic inflammation, focused on three specific biomarkers (CRP, IL-8 and TNF-α), and risk of pancreatic cancer have reported no associations. In this study, we evaluated associations between standard pre-diagnostic serum markers of chronic inflammation (CRP, albumin, haptoglobin and leukocytes) and pancreatic cancer risk in the Swedish Apolipoprotein-related MORtality RISk (AMORIS) prospective cohort study. METHODS: We selected all participants (≥20 years old) with baseline measurements of CRP, albumin, haptoglobin and leukocytes between 1985 and 1996 (n = 61,597). Participants were excluded if they had a history of chronic pancreatitis and all individuals were free from pancreatic cancer at baseline. Cox proportional multivariable hazards regression analysis was carried out for medical cut-offs of CRP, albumin, haptoglobin and leukocytes. RESULTS: We observed an increased risk of pancreatic cancer for those individuals with higher levels of serum haptoglobin (≥1.4 g/L), CRP (≥10 mg/L) and leukocytes (≥10 × 109 cells/L) compared to those with haptoglobin levels < 1.4 g/L, CRP levels < 10 mg/L and Leukocyte levels < 10 × 109 cells/L [haptoglobin HR: 2.23 (95% CI 1.72-2.88), CRP HR: 1.32 (95% CI 1.00-1.74), leukocytes HR: 2.20 (95% CI 1.52-3.18)]. No associations were noted for serum albumin. CONCLUSIONS: We found an increased risk of pancreatic cancer associated with pre-diagnostic serum levels of haptoglobin, CRP and leukocytes. Our finding suggests a possible role of chronic inflammation in the aetiology of pancreatic cancer and highlight the need to further investigate this association.
doi: https://doi.org/10.1186/s12885-019-6082-6
- High Co-expression of Large Tenascin C Splice Variants in Stromal Tissue and Annexin A2 in Cancer Cell Membranes is Associated with Poor Prognosis in Pancreatic Cancer
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31463696
BACKGROUND: Pancreatic cancer tissue contains abundant stromal components, including extracellular matrix proteins such as tenascin C (TNC), which exists as large (TNC-L) and non-large splice variants. Here, we examined human pancreatic cancer specimens for the expression of total TNC (TNC-ALL) and TNC-L in the stroma and annexin A2 (ANXA2), a cell surface receptor for TNC, and evaluated their significance as prognostic markers for pancreatic cancer. METHODS: Expression of ANXA2, TNC-ALL, and TNC-L was examined in 106 pancreatic cancer tissues from patients who underwent curative resection and who had not received prior therapy or surgery. Protein expression was measured by immunohistochemistry and scored on a semi-quantitative scale. The relationships between protein expression, clinicopathological factors, and prognosis were evaluated by Cox proportional hazards analysis. RESULTS: TNC-ALL and TNC-L were detected mainly in the stroma, whereas ANXA2 was predominantly expressed in cancer cell membranes. TNC-ALL was also expressed in non-tumor pancreatic tissue. High levels of stromal TNC-L and membranous ANXA2, but not stromal TNC-ALL, were independently associated with cancer progression and poor prognosis. Moreover, high co-expression of stromal TNC-L and membranous ANXA2 was a superior indicator of poor prognosis compared with detection of TNC-ALL, TNC-L, or ANXA2 alone. CONCLUSIONS: Our data suggest that co-expression of stromal TNC-L and membranous ANXA2 is a poor prognostic marker compared with detection of TNC-L or ANXA2 alone for pancreatic cancer patients. Additionally, targeting of crosstalk between stromal TNC and cancer cell ANXA2 could be a promising therapeutic strategy to overcome refractory pancreatic cancer.
doi: https://doi.org/10.1245/s10434-019-07708-x
- Deficits in the Palliative Care Process Measures in Patients with Advanced Pancreatic Cancer Undergoing Operative and Invasive Nonoperative Palliative Procedures
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31463695
BACKGROUND: Given survival measured in months, metrics, such as 30-day mortality, are poorly suited to measure the quality of palliative procedures for patients with advanced cancer. Nationally endorsed process measures associated with high-quality PC include code-status clarification, goals-of-care discussions, palliative-care referral, and hospice assessment. The impact of the performance of these process measures on subsequent healthcare utilization is unknown. METHODS: Administrative data and manual review were used to identify hospital admissions with performance of palliative procedures for advanced pancreatic cancer at two tertiary care hospitals from 2011 to 2016. Natural language processing, a form of computer-assisted abstraction, identified process measures in associated free-text notes. Healthcare utilization was compared using a Cox proportional hazard model. RESULTS: We identified 823 hospital admissions with performance of a palliative procedure. PC process measures were identified in 68% of admissions. Patients with documented process measures were older (66 vs. 63; p = 0.04) and had a longer length of stay (9 vs. 6 days; p < 0.001). In multivariate analysis, patients treated by surgeons were less likely to have PC process measures performed (odds ratio 0.19; 95% confidence interval 0.10-0.37). Performance of PC process measures was associated with decreased healthcare utilization in a Cox proportional hazard model. CONCLUSIONS: PC process measures were not performed in almost one-third of hospital admissions for palliative procedures in patients with advanced pancreatic cancer. Performance of established high-quality process measures for seriously ill patients undergoing palliative procedures may help patients to avoid burdensome, high-intensity care at the end-of-life.
doi: https://doi.org/10.1245/s10434-019-07757-2
- ASO Author Reflections: Formalization of Robotic Central Pancreatectomy Focusing on the Reconstruction of Pancreatic Digestive Continuity
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31463694
doi: https://doi.org/10.1245/s10434-019-07774-1
- Whole-genome sequencing reveals distinct genetic bases for insulinomas and non-functional pancreatic neuroendocrine tumours: leading to a new classification system
Gut 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31462556
OBJECTIVE: Insulinomas and non-functional pancreatic neuroendocrine tumours (NF-PanNETs) have distinctive clinical presentations but share similar pathological features. Their genetic bases have not been comprehensively compared. Herein, we used whole-genome/whole-exome sequencing (WGS/WES) to identify genetic differences between insulinomas and NF-PanNETs. DESIGN: The mutational profiles and copy-number variation (CNV) patterns of 211 PanNETs, including 84 insulinomas and 127 NF-PanNETs, were obtained from WGS/WES data provided by Peking Union Medical College Hospital and the International Cancer Genome Consortium. Insulinoma RNA sequencing and immunohistochemistry data were assayed. RESULTS: PanNETs were categorised based on CNV patterns: amplification, copy neutral and deletion. Insulinomas had CNV amplifications and copy neutral and lacked CNV deletions. CNV-neutral insulinomas exhibited an elevated rate of YY1 mutations. In contrast, NF-PanNETs had all three CNV patterns, and NF-PanNETs with CNV deletions had a high rate of loss-of-function mutations of tumour suppressor genes. NF-PanNETs with CNV alterations (amplification and deletion) had an elevated risk of relapse, and additional DAXX/ATRX mutations could predict an increased relapse risk in the first 2-year period. CONCLUSION: These WGS/WES data allowed a comprehensive assessment of genetic differences between insulinomas and NF-PanNETs, reclassifying these tumours into novel molecular subtypes. We also proposed a novel relapse risk stratification system using CNV patterns and DAXX/ATRX mutations.
doi: https://doi.org/10.1136/gutjnl-2018-317233
- Cell block processing is optimal for assessing endoscopic ultrasound fine needle aspiration specimens of pancreatic mucinous cysts
Journal of clinical pathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31462450
AIMS: The cell block technique for assessing endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) specimens from pancreatic mucinous cystic lesions (MCLs) was systematically evaluated for the first time, including comparisons with three traditional methods of assessing such specimens. METHODS: The prospective arm comprised EUS-FNA specimens from EUS-suspected pancreatic MCLs. The retrospective arm comprised EUS-FNA specimens from pancreatic MCLs surgically resected before the study start. For each specimen, these data points were collected: macroscopic likelihood of mucin, cyst fluid carcinoembryonic antigen (CEA) level and presence of mucin in air-dried, direct smears and in cell block preparations. RESULTS: The prospective and retrospective arms of the study comprised 80 and 30 EUS-FNA specimens, respectively. Seven prospective cases led to surgical resections during the study, and therefore, 37 EUS-FNA specimens were confirmed to have originated from MCLs. In the prospective arm, macroscopic mucin was suspected, cyst fluid CEA level exceeded 192 ng/mL, mucin was detected in direct smears and cell block preparations in 78%, 30%, 39% and 73% of cases, respectively. Of the 37 specimens confirmed to originate from MCLs, macroscopic mucin assessment, cyst fluid CEA level, direct smear mucin assessment and cell block mucin assessment had sensitivities for diagnosing MCL of 87%, 45%, 45% and 81%, respectively. CONCLUSIONS: Cell block preparations are as likely to identify mucin from pancreatic MCLs as macroscopic assessment but are twice as likely to diagnose MCL than direct smears and fluid CEA biochemistry. The cell block technique is easy for sample collection and processing especially because these are identical for solid and cystic pancreatic lesions.
doi: https://doi.org/10.1136/jclinpath-2019-206079
- Pancreatic calcifications associate with diverse aetiological risk factors in patients with chronic pancreatitis: A multicentre study of 1500 cases
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31462382
BACKGROUND: Pancreatic calcifications is a common finding in patients with chronic pancreatitis (CP), but the underlying pathophysiology is incompletely understood. Past studies for risk factors of calcifications have generally been focused on single parameters or limited by small sample sizes. The aim of this study was to explore several patient and disease characteristics and their associations with pancreatic calcifications in a large cohort of CP patients with diverse aetiological risk factors. METHODS: This was a multicentre, cross-sectional study including 1509 patients with CP. Patient and disease characteristics were compared for patients with calcifications (n = 912) vs. without calcifications (n = 597). Multivariable logistic regression was performed to assess the parameters independently associated with calcifications. RESULTS: The mean age of patients was 53.9 ± 14.5 years and 1006 (67%) were men. The prevalence of calcifications was 60.4% in the overall patient cohort, but highly variable between patients with different aetiological risk factors (range: 2-69%). On multivariate analysis, alcoholic aetiology (OR 1.76 [95% CI, 1.39-2.24]; p < 0.001) and smoking aetiology (OR 1.77 [95% CI, 1.39-2.26], p < 0.001) were positively associated with the presence of calcifications, while an autoimmune aetiology was negatively associated with calcifications (OR 0.15 [95% CI, 0.08-0.27], p < 0.001). Patients with pancreatic calcifications were more likely to have undergone pancreatic duct stenting (OR 1.59 [95%CI, 1.16-2.19], p = 0.004). CONCLUSION: The presence of pancreatic calcifications is associated with diverse aetiological risk factors in patients with CP. This observation attest to the understanding of CP as a complex disease and may have implications for disease classification.
doi: https://doi.org/10.1016/j.pan.2019.08.009
- Comparative efficacy and tolerability of front-line treatments for newly diagnosed chronic-phase chronic myeloid leukemia: an update network meta-analysis
BMC cancer 2019 Aug;19(1):849
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31462241
BACKGROUND: Recent years have witnessed the rapid evolution of therapies in chronic-phase chronic myeloid leukemia (CP-CML). To assess the efficacy and tolerability of all reported front-line treatments for patients with newly diagnosed CML, a multiple-treatments meta-analysis was performed, which accounted for both direct and indirect comparisons among those treatments. METHODS: Primary outcomes were the percentage of patients achieving major molecular response (MMR) and complete cytogenetic response (CCyR) within 12 months. Secondary outcomes included the percentage of progression to accelerated phase (AP), serious adverse effects (AEs), overall discontinuation and discontinuation for drug-related AEs. Direct pairwise meta-analysis and indirect multi-comparison meta-analysis among those treatments in each outcome were both conducted. The surface under the cumulative ranking curve (SUCRA) was calculated for all treatments in each outcome. Cluster analysis demonstrated the division of treatments into distinct groupings according to efficacy and tolerability profiles. RESULTS: A total of 21 randomized controlled trials (RCTs, including 10,187 patients) comparing 15 different interventions for CP-CML patients were included in this study. SUCRA analysis suggested that all tyrosine kinase inhibitors (TKIs) are highly effective in newly diagnosed CP-CML when compared to traditional drugs. Newer TKIs and higher-dose imatinib generally resulted in faster cytogenetic and molecular responses when compared with standard-dose imatinib and traditional drugs. Furthermore, traditional drugs, higher-dose imatinib and newer TKIs demonstrated lower acceptability than standard-dose imatinib. One cluster of interventions, which included nilotinib (300/400 mg BID), dasatinib (100 mg QD) and radotinib (300 mg BID), demonstrated higher efficacy and tolerability than other treatments. CONCLUSIONS: Nilotinib (300/400 mg BID), dasatinib (100 mg QD) and radotinib (300 mg BID) prove to be the most recommended front-line treatments of the greatest efficacy and tolerability for CP-CML patients. High-dose therapies are recommended only for patients in accelerated phase/blast phase or with suboptimal CML-CP response, and management of adverse events should be carried out to avoid compromising the clinical efficacy.
doi: https://doi.org/10.1186/s12885-019-6039-9
- Preoperative Risk Assessment for Loss of Independence Following Hepatic Resection in Elderly Patients: A Prospective Multicenter Study
Annals of surgery 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31460876
OBJECTIVE: To establish a preoperative risk assessment method for loss of independence after hepatic resection. SUMMARY BACKGROUND DATA: Hepatic resection often results in loss of independence in preoperatively self-sufficient elderly people. Elderly patients should therefore be carefully selected for surgery. METHODS: In this prospective, multicenter study, 347 independently-living patients aged ≥65 years, scheduled for hepatic resection, were divided into study (n = 232) and validation (n = 115) cohorts. We investigated the risk factors for postoperative loss of independence in the study cohort and verified our findings with the validation cohort. Loss of independence was defined as transfer to a rehabilitation facility, discharge to residence with home-based healthcare, 30-day readmission for poor functionality, and 90-day mortality (except for cancer-related deaths). RESULTS: In the study cohort, univariate and multivariate analyses indicated that frailty, age ≥ 76 years, and open surgery were independent risk factors for postoperative loss of independence. Proportions of patients with postoperative loss of independence in the study and validation cohorts were respectively 3.0% and 0% among those with no applicable risk factors, 8.1% and 12.5% among those with 1 applicable risk factor, 25.5% and 25.0% among those with 2 applicable risk factors, and 56.3% and 50.0% among those with all 3 factors applicable (P < 0.001 for both cohorts). Areas under the receiver operating characteristic curves for the study and validation groups were 0.777 and 0.783, respectively. CONCLUSIONS: Preoperative risk assessments using these 3 factors may be effective in predicting and planning for postoperative loss of independence after hepatic resection in elderly patients.
doi: https://doi.org/10.1097/SLA.0000000000003585
- An analysis of genetic heterogeneity in untreated cancers
Nature reviews. Cancer 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31455892
Genetic intratumoural heterogeneity is a natural consequence of imperfect DNA replication. Any two randomly selected cells, whether normal or cancerous, are therefore genetically different. Here, we review the different forms of genetic heterogeneity in cancer and re-analyse the extent of genetic heterogeneity within seven types of untreated epithelial cancers, with particular regard to its clinical relevance. We find that the homogeneity of predicted functional mutations in driver genes is the rule rather than the exception. In primary tumours with multiple samples, 97% of driver-gene mutations in 38 patients were homogeneous. Moreover, among metastases from the same primary tumour, 100% of the driver mutations in 17 patients were homogeneous. With a single biopsy of a primary tumour in 14 patients, the likelihood of missing a functional driver-gene mutation that was present in all metastases was 2.6%. Furthermore, all functional driver-gene mutations detected in these 14 primary tumours were present among all their metastases. Finally, we found that individual metastatic lesions responded concordantly to targeted therapies in 91% of 44 patients. These analyses indicate that the cells within the primary tumours that gave rise to metastases are genetically homogeneous with respect to functional driver-gene mutations, and we suggest that future efforts to develop combination therapies have the potential to be curative.
doi: https://doi.org/10.1038/s41568-019-0185-x
- A phase 1 study of the anti-CC chemokine receptor 4 antibody, mogamulizumab, in combination with nivolumab in patients with advanced or metastatic solid tumors
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31455681
PURPOSE: Regulatory T-cells (Tregs) expressing CC chemokine receptor 4 (CCR4) can suppress antitumor immune responses and are associated with poor prognoses in several cancers. We assessed the safety and efficacy of combined mogamulizumab (anti-CCR4 antibody) and nivolumab (anti-programmed death-1 [PD-1] antibody) in immunotherapy-naive patients with advanced/metastatic solid tumors. EXPERIMENTAL DESIGN: This study (NCT02476123) comprised dose-escalation (3+3 design) and expansion parts. Patients received nivolumab (3.0 mg/kg) every 2 weeks, with mogamulizumab (0.3 or 1.0 mg/kg in dose-escalation, 1.0 mg/kg in expansion) once weekly for 4 weeks, then every 2 weeks, until progression or unacceptable toxicity. Primary objective was safety; secondary objectives were antitumor effects, pharmacokinetics, and immunogenicity. Exploratory biomarker analyses were conducted. RESULTS: 96 patients were enrolled (July 2015-November 2016): six patients in the dose-escalation part and 90 in the expansion part. No dose-limiting toxicities were observed in the dose-escalation part. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculo-papular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%). There were four (27%) confirmed tumor responses among 15 patients with hepatocellular carcinoma, and one confirmed and two unconfirmed responses among 15 patients with pancreatic adenocarcinoma. During treatment, populations of effector Tregs (CD4+CD45RA-FoxP3high) decreased and CD8+ T-cells in tumor-infiltrating lymphocytes increased. CONCLUSIONS: Combining an anti-PD-1 antibody, nivolumab, with a Treg-depleting anti-CCR4 antibody, mogamulizumab, provides an acceptable safety profile, antitumor activity, and a potentially effective option in cancer immunotherapy.
doi: https://doi.org/10.1158/1078-0432.CCR-19-1090
- Allosteric modulation of β-cell M3 muscarinic acetylcholine receptors greatly improves glucose homeostasis in lean and obese mice
Proceedings of the National Academy of Sciences of the United States of America 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31451647
Given the global epidemic in type 2 diabetes, novel antidiabetic drugs with increased efficacy and reduced side effects are urgently needed. Previous work has shown that M3 muscarinic acetylcholine (ACh) receptors (M3Rs) expressed by pancreatic β cells play key roles in stimulating insulin secretion and maintaining physiological blood glucose levels. In the present study, we tested the hypothesis that a positive allosteric modulator (PAM) of M3R function can improve glucose homeostasis in mice by promoting insulin release. One major advantage of this approach is that allosteric agents respect the ACh-dependent spatiotemporal control of M3R activity. In this study, we first demonstrated that VU0119498, a drug known to act as a PAM at M3Rs, significantly augmented ACh-induced insulin release from cultured β cells and mouse and human pancreatic islets. This stimulatory effect was absent in islets prepared from mice lacking M3Rs, indicative of the involvement of M3Rs. VU0119498 treatment of wild-type mice caused a significant increase in plasma insulin levels, accompanied by a striking improvement in glucose tolerance. These effects were mediated by β-cell M3Rs, since they were absent in mutant mice selectively lacking M3Rs in β cells. Moreover, acute VU0119498 treatment of obese, glucose-intolerant mice triggered enhanced insulin release and restored normal glucose tolerance. Interestingly, doses of VU0119498 that led to pronounced improvements in glucose homeostasis did not cause any significant side effects due to activation of M3Rs expressed by other peripheral cell types. Taken together, the data from this proof-of-concept study strongly suggest that M3R PAMs may become clinically useful as novel antidiabetic agents.
doi: https://doi.org/10.1073/pnas.1904943116
- “Trivial” Cysts Redefine the Risk of Cancer in Presumed Branch-Duct Intraductal Papillary Mucinous Neoplasms of the Pancreas: A Potential Target for Follow-Up Discontinuation?
The American journal of gastroenterology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31449158
OBJECTIVES: The management of small and incidental branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) still is of concern. The aim is assessing the safety of a surveillance protocol through the evaluation of their progression to malignancy. METHODS: All presumed BD-IPMNs observed from 2000 to 2016 were included. Only patients presenting without worrisome features (WFs) and high-risk stigmata (HRS) at diagnosis were included. Development of WF, HRS, pancreatic cancer (PC), and survival were analyzed. BD-IPMNs were defined as trivial in the continuing absence of WF/HRS after 5 years of surveillance. The age-specific standardized incidence ratio of PC in the general population was used for comparison. RESULTS: A total of 1,036 BD-IPMNs without WF/HRS at diagnosis were included, 4.2% developed WF or HRS, and 1.1% developed PC after a median of 62 months. The median cyst growth rate was 0 mm/yr. A growth rate ≥2.5 mm/yr and the development of WF resulted independent predictors of PC. The standardized incidence ratio of PC for trivial BD-IPMN (n = 378) was 22.45 (95% confidence interval 8.19-48.86), but considering only patients aged >65 years (n = 198), it decreased to 3.84 (95% confidence interval 0.77-11.20). DISCUSSION: Surveillance of the vast majority of presumed BD-IPMNs is safe, as the risk of PC is comparable to postoperative mortality of pancreatic surgery. A growth rate ≥2.5 mm/yr is the main predictor of PC, reinforcing the role of repeated observations. A trivial BD-IPMN in patients aged >65 years might not increase the risk of developing PC compared with general population, identifying potential targets for follow-up discontinuation.
doi: https://doi.org/10.14309/ajg.0000000000000378
- Management of Locally Advanced Pancreatic Cancer: Results of an International Survey of Current Practice
Annals of surgery 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31449138
MINI: An international survey of high-volume pancreas cancer surgeons revealed wide variations in management preferences, attitudes regarding contraindications to surgery, and the propensity to offer exploration. When presented with 6 hypothetical clinical vignettes using details from real patients that have received R0 resection, only 14% to 53% of participating surgeons were willing to offer exploration following neoadjuvant therapy. The aim of this study was to investigate surgeon preferences for the management of patients with locally advanced pancreatic cancer (LAPC). Select patients with LAPC may become candidates for curative resection following neoadjuvant therapy, and recent reports of survival are encouraging. Yet the optimal management approach remains unclear. An extensive electronic survey was systematically distributed by email to an international cohort of pancreas surgeons. Data collected included practice characteristics, management preferences, attitudes regarding contraindications to surgery, and 6 clinical vignettes of patients that ultimately received a margin negative resection (with detailed videos of post-neoadjuvant imaging) to assess propensity for surgical exploration if resection status is not known. A total of 153 eligible responses were received from 4 continents. Median duration of practice is 12 years (interquartile range 6-20) and 77% work in a university setting. Most surgeons (86%) are considered high volume (>10 resections/yr), 33% offer a minimally-invasive approach, and 50% offer arterial resections in select patients. Most (72%) always recommend neoadjuvant chemotherapy, and 65% prefer FOLFIRINOX. Preferences for the duration of chemotherapy varied widely: 39% prefer ≥2 months, 43% prefer ≥4 months, and 11% prefer ≥6 months. Forty-one percent frequently recommend neoadjuvant radiotherapy, and 53% prefer 5 to 6 weeks of chemoradiation. The proportion of surgeons favoring exploration following neoadjuvant varied extensively across 5 vignettes of LAPC, from 14% to 53%. In a vignette of oligometastatic liver metastases, 31% would offer exploration if a favorable therapy response is observed. In an international cohort of pancreas surgeons, there is substantial variation in management preferences, perceived contraindications to surgery, and the propensity to consider exploration in LAPC. These results emphasize the importance of a robust and nuanced multidisciplinary discussion for each patient, and suggest an evolving concept of “resectability.”
doi: https://doi.org/10.1097/SLA.0000000000003568
- New High-throughput Screen Identifies Compounds That Reduce Viability Specifically In Liver Cancer Cells That Express High Levels of SALL4 by Inhibiting Oxidative Phosphorylation
Gastroenterology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31446059
BACKGROUND AND AIMS: Some oncogenes encode transcription factors, but few drugs have been successfully developed to block their activity specifically in cancer cells. The transcription factor SALL4 is aberrantly expressed in solid tumor and leukemia cells. We developed a screen to identify compounds that reduce the viability of liver cancer cells that express high levels of SALL4 and we investigated their mechanisms. METHODS: We developed a stringent high-throughput screening platform comprising unmodified SNU-387 and SNU-398 liver cancer cell lines and SNU-387 cell lines engineered to express low and high levels of SALL4. We screened 1597 pharmacologically active small molecules and 21,575 natural product extracts from plant, bacteria, and fungal sources for those that selectively reduce the viability of cells with high levels of SALL4 (SALL4hi cells). We compared gene expression patterns of SALL4hi cells vs SALL4-knockdown cells using RNA-seq and real-time PCR analyses. Xenograft tumors were grown in NOD/SCID gamma mice from SALL4hi SNU-398 or HCC26.1 cells or from SALL4lo PDX cells; mice were given injections of identified compounds or sorafenib and the effects on tumor growth were measured. RESULTS: Our screen identified 1 small molecule (PI-103) and 4 natural compound analogues (oligomycin, efrapeptin, antimycin, and leucinostatin) that selectively reduced viability of SALL4hi cells. We performed validation studies, and 4 of these compounds were found to inhibit oxidative phosphorylation. The ATP synthase inhibitor oligomycin reduced the viability of SALL4hi hepatocellular carcinoma and non-small-cell lung cancer cell lines with minimal effects on SALL4lo cells. Oligomycin also reduced the growth of xenograft tumors grown from SALL4hi SNU-398 or HCC26.1 cells, to a greater extent than sorafenib, but oligomycin had little effect on tumors grown from SALL4lo PDX cells. Oligomycin was not toxic to mice. Analyses of chromatin immunoprecipitation sequencing data revealed that SALL4 binds approximately 50% of mitochondrial genes, including many oxidative phosphorylation genes, to activate their transcription. In comparing SALL4hi and SALL4-knockdown cells, we found SALL4 to increase oxidative phosphorylation, oxygen consumption rate, mitochondrial membrane potential, and utilization of oxidative phosphorylation-related metabolites to generate ATP. CONCLUSIONS: In a screen for compounds that reduce the viability of cells that express high levels of the transcription factor SALL4, we identified inhibitors of oxidative phosphorylation, which slowed the growth of xenograft tumors from SALL4hi cells in mice. SALL4 activates transcription of genes that regulate oxidative phosphorylation to increase oxygen consumption, mitochondrial membrane potential, and ATP generation in cancer cells. Inhibitors of oxidative phosphorylation might be used for treatment of liver tumors with high levels of SALL4.
doi: https://doi.org/10.1053/j.gastro.2019.08.022
- Primary pancreatic diffuse large B-cell lymphoma diagnosed by endoscopic ultrasound guided FNAC: A rare entity
Diagnostic cytopathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31444945
Primary pancreatic lymphoma (PPL) is an uncommon neoplasm which can clinico-radiologically mimic carcinoma. But the management of these patients differs from that of a carcinoma. Endoscopic ultrasound (EUS) guided fine-needle aspiration (FNA) serves as a potential tool to identify pancreatic lymphomas and thus prevent an invasive diagnostic test. This case report describes the presentation and diagnosis of primary pancreatic lymphoma. A 37-year-old female presented with nausea, vomiting with signs of icterus and elevated liver function test and Bilirubin. Abdominal computed tomography (CT) revealed a hypodense lesion in the head of the pancreas. EUS guided FNA was performed and cytological material was collected. The lesion was diagnosed as Non-Hodgkin Lymphoma (NHL) and subtyped as diffuse large B-cell lymphoma-germinal centre (DLBCL-GCB) base on immunohistochemistry on cell block. The patient was started on rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (RCHOP) regimen. EUS guided FNA along with ROSE, cell bock, and immunocytochemistry helps in the diagnosis of primary pancreatic lymphoma.
doi: https://doi.org/10.1002/dc.24307
- Dynamic Changes in Normal Liver Parenchymal Volume During Chemotherapy for Colorectal Cancer: Liver Atrophy as an Alternate Marker of Chemotherapy-Associated Liver Injury
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31440929
BACKGROUND: The purpose of this study was to investigate the incidence, origin, and clinical significance of liver atrophy during chemotherapy for colorectal cancer. METHODS: This study included 103 patients who underwent chemotherapy before resection for colorectal liver metastases (training set) and 171 patients who underwent adjuvant or first-line chemotherapy without liver resection (validation set). A greater than 10% decrease (atrophy) or increase (hypertrophy) of the liver volume from the baseline was defined as a significant change. RESULTS: In the training set, the numbers of patients who developed atrophy, no change of volume, and hypertrophy of the liver after chemotherapy were 15 (14.6%), 73 (70.9%), and 15 (14.6%), respectively. Liver atrophy was associated with impaired hepatic function, and the postoperative morbidity rate and refractory ascites/pleural effusion were higher in the patients with liver atrophy than those without (60.0% vs. 31.8%, P = 0.045 and 46.7% vs. 8.0%, P < 0.001, respectively). Histopathological examination revealed a strong association between sinusoidal injury and liver atrophy (P < 0.001). The cumulative incidence of liver atrophy increased with increasing duration of chemotherapy, whereas the incidence of liver atrophy was less frequent in patients who had received bevacizumab than those who had not in both the training set (odds ratio [OR], 0.13; P = 0.001) and the validation set (OR, 0.31; P = 0.007). CONCLUSIONS: Liver atrophy is associated with impaired hepatic functional reserve and observed at an increasing frequency as the duration of chemotherapy increases with frequent histopathological evidence of sinusoidal injury in the liver. Bevacizumab may protect against the development of liver atrophy.
doi: https://doi.org/10.1245/s10434-019-07740-x
- A Prospective, Open-Label, Multicenter Phase 2 Trial of Neoadjuvant Therapy Using Full-Dose Gemcitabine and S-1 Concurrent with Radiation for Resectable Pancreatic Ductal Adenocarcinoma
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31440928
BACKGROUND: Neoadjuvant therapy reportedly shows only marginal clinical benefit in pancreatic ductal adenocarcinoma (PDAC), especially in resectable cases. However, with more effective regimens, neoadjuvant therapy may become a standard of care for resectable cases. A prospective, open-label, multicenter phases 1 and 2 trial of neoadjuvant therapy was conducted using full-dose gemcitabine and S-1 concurrently with 50.4 Gy of radiation therapy (GSRT) for resectable PDAC. This report describes the phase 2 results. METHODS: The phase 2 part of this study enrolled 57 patients with cytologically or histologically proven PDAC deemed resectable based on imaging before neoadjuvant therapy. These patients received GSRT. After reevaluation by computed tomography scan, surgical exploration was performed, followed by adjuvant therapy. According to the prescribed protocol of the clinical trial, statistical analyses included 57 phase 2 patients and 6 phase 1 patients who received the same dosage as in phase 2. RESULTS: This trial enrolled 63 patients (42 men and 21 women) with a median age of 70 years. Leukopenia or neutropenia of grade 3 or higher occurred for 79% of the patients, but no other severe adverse events were observed. Among the 63 patients, 54 underwent surgical resection. Intention-to-treat analysis of the 63 patients showed an excellent median survival time lasting as long as 55.3 months. The patients who completed neoadjuvant therapy, surgery, and adjuvant therapy had a 5-year survival rate of 56.6%. CONCLUSIONS: This regimen showed outstanding clinical efficacy with acceptable tolerability for patients with resectable PDAC.
doi: https://doi.org/10.1245/s10434-019-07735-8
- ASO Author Reflections: Lymph Node Metastasis and the Role for Lymphadenectomy During Surgery for Nonfunctional Pancreatic Neuroendocrine Tumors
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31440924
doi: https://doi.org/10.1245/s10434-019-07746-5
- Editorial About: “A Prospective, Open-Label, Multicenter Phase II Trial of Neoadjuvant Therapy Using Full-Dose Gemcitabine and S-1 Concurrent with Radiation for Resectable Pancreatic Ductal Adenocarcinoma”
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31440923
doi: https://doi.org/10.1245/s10434-019-07737-6
- Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma
Proceedings of the National Academy of Sciences of the United States of America 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31439820
Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and are currently in clinical development in melanoma, a tumor that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib and demonstrate that the activity of PRMT5, a protein arginine methyltransferase and indirect target of CDK4, is essential for CDK4/6 inhibitor sensitivity. By indirectly suppressing PRMT5 activity, palbociclib alters the pre-mRNA splicing of MDM4, a negative regulator of p53, leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 induces p21, leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5-MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treating naive and resistant models and also delays the emergence of resistance. Our studies have uncovered a mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5-MDM4 axis is essential for robust melanoma cell sensitivity and provide preclinical evidence that coinhibition of CDK4/6 and PRMT5 is an effective and well-tolerated therapeutic strategy. Overall, our data provide a strong rationale for further investigation of novel combinations of CDK4/6 and PRMT5 inhibitors, not only in melanoma but other tumor types, including breast, pancreatic, and esophageal carcinoma.
doi: https://doi.org/10.1073/pnas.1901323116
- Phase I Trial of Well-Differentiated Neuroendocrine Tumors (NETs) with Radiolabeled Somatostatin Antagonist 177 Lu-Satoreotide Tetraxetan
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31439583
PURPOSE: Radiolabeled somatostatin receptor 2 (SSTR2) antagonists have shown higher tumor uptake and tumor-to-organ ratios than somatostatin agonists in preclinical models of NETs. We performed a phase I study to evaluate the safety and efficacy of SSTR2 antagonist 177Lu-satoreotide tetraxetan. EXPERIMENTAL DESIGN: Twenty patients with advanced SSTR2 positive NETs were treated with 177Lu-satoreotide tetraxetan. Patients first underwent a dosimetry study with 177Lu-satoreotide tetraxetan to determine the therapeutic activity that could be safely administered. This activity was split into two equal cycles to be delivered three months apart. The maximum activity was 7.4 GBq per cycle. RESULTS: Of 20 NET patients (1 lung, 7 small bowel, 9 pancreatic, 1 gastric, 1 rectal, 1 kidney; mean prior treatments: 3), 6 received one cycle of 177Lu- satoreotide tetraxetan and 14 received two cycles. Hematologic toxicity after cycle 1 was mild-moderate and reversed before cycle 2. However, grade 4 hematologic toxicity occurred in 4/7 (57%) patients after cycle 2 of 177Lu-satoreotide tetraxetan. The study was suspended, and the protocol modified to limit the cumulative absorbed bone marrow dose to 1Gy and to reduce prescribed activity for cycle 2 by 50%. The best overall response rate was 45% (5% complete response (1/20), 40% partial response (8/20)); with 40% stable disease (8/20) and 15% progression of disease (3/20). Median progression-free survival (PFS) was 21.0 months (95% CI: 13.6-NR). CONCLUSION: In this trial of heavily treated NETs, preliminary data are promising for the use of 177Lu-satoreotide tetraxetan. Additional studies are on-going to determine optimal therapeutic dose/schedule.
doi: https://doi.org/10.1158/1078-0432.CCR-19-1026
- AZD1775 plus chemoradiotherapy for pancreatic cancer
The Lancet. Oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31427207
doi: https://doi.org/10.1016/S1470-2045(19)30537-6
- Acute Pancreatitis Associated With Myotonic Dystrophy Type I
Pancreas 2019 Sep;48(8):e63-e64
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31425487
doi: https://doi.org/10.1097/MPA.0000000000001366
- Minimally Invasive Treatment for Severe Acute Pancreatitis With Superior Mesenteric Vein and Common Bile Duct Stenosis: A Case Report and Review of the Literature
Pancreas 2019 Sep;48(8):e61-e63
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31425486
doi: https://doi.org/10.1097/MPA.0000000000001379
- Clinical Utility of Cytokine Biomarker Analysis of Pancreatic Cyst Fluid Obtained by Endoscopic Ultrasound Fine Needle Aspiration: A Pilot Study
Pancreas 2019 Sep;48(8):e60-e61
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31425485
doi: https://doi.org/10.1097/MPA.0000000000001365
- Cigarette Smoking and Mortality in Patients With Pancreatic Cancer: A Systematic Review and Meta-analysis
Pancreas 2019 Sep;48(8):985-995
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31425484
Current evidence on cigarette smoking associated with pancreatic cancer mortality is limited. We searched MEDLINE, Web of Science, and Embase databases to identify relevant studies published through January 31, 2018. A random-effects model was used to estimate summary hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 20 studies were retrieved, involving 2,517,623 participants. Of these, more than 15,341 patients with pancreatic cancer died. Compared with never smokers, current (summary HR, 1.56; 95% CI, 1.34-1.83) and former (summary HR, 1.15; 95% CI, 1.06-1.26) smokers had elevated risk of total mortality in patients diagnosed with pancreatic cancer. This effect of cigarette smoking is observed both in the Western regions and the Asia-Pacific regions. This effect of smoking is independent of alcohol use, body mass index, and history of diabetes but is modified by tumor stage and study settings. Dose-response associations between smoking and pancreatic cancer mortality were revealed for smoking intensity, cumulative amount of cigarettes smoked, and duration of smoking. Cigarette smoking was associated with an increase in total mortality for patients with pancreatic cancer. Future studies should further clarify the role of smoking as an effect modifier in treatment trials of pancreatic cancer.
doi: https://doi.org/10.1097/MPA.0000000000001383
- A Qualitative Review of Neoadjuvant Chemotherapy in Resectable Pancreatic Adenocarcinoma
Pancreas 2019 Sep;48(8):973-984
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31425483
The aim of this study was to evaluate outcomes of patients with resectable pancreatic adenocarcinoma (PDAC) who underwent neoadjuvant chemotherapy. The MEDLINE and PubMed databases were searched to identify relevant original articles investigating neoadjuvant therapy in resectable PDAC. Qualitative analyses were performed to investigate patient selection, disease stage, impact on perioperative outcomes, and cost-effectiveness. Forty-three studies met inclusion criteria for this review. Neoadjuvant chemotherapy for upfront resectable PDAC is cost-effective, safe, may result in lower stage disease and has potential survival advantages. With proper patient selection, neoadjuvant chemotherapy is an appropriate approach for upfront resectable PDAC. Nevertheless, the risk for disease progression and losing a curative surgical window highlights the need for appropriate patient identification, further discovery of superior biomarkers or molecular profiles representative of positive treatment response, and additional prospective comparative study.
doi: https://doi.org/10.1097/MPA.0000000000001376
- Management of Diarrhea in Patients With Carcinoid Syndrome
Pancreas 2019 Sep;48(8):961-972
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31425482
Neuroendocrine tumors (NETs) arise from enterochromaffin cells found in neuroendocrine tissues, with most occurring in the gastrointestinal tract. The global incidence of NETs has increased in the past 15 years, likely due to better diagnostic methods. Small-bowel NETs are frequently associated with carcinoid syndrome (CS). Carcinoid syndrome diarrhea occurs in 80% of CS patients and poses a substantial symptomatic and economic burden. Patients with CS diarrhea frequently suffer from diarrhea and flushing and report corresponding impairment in quality of life, requiring substantial changes in daily activities and lifestyle. Treatment paradigms range from surgical debulking to liver-directed therapies to treatment with somatostatin analogs, nonspecific anti-diarrheal agents, and a tryptophan hydroxylase inhibitor. Other causes of diarrhea, including steatorrhea, short bowel syndrome, and bile acid malabsorption, should be considered in NET patients with refractory diarrhea. More therapeutic options are needed for symptomatic management of patients with NETs, and better understanding of the pathophysiology can empower clinicians with improved patient care.
doi: https://doi.org/10.1097/MPA.0000000000001384
- Cell phenotypic plasticity requires autophagic flux driven by YAP/TAZ mechanotransduction
Proceedings of the National Academy of Sciences of the United States of America 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31416916
Autophagy, besides ensuring energy metabolism and organelle renewal, is crucial for the biology of adult normal and cancer stem cells. However, it remains incompletely understood how autophagy connects to stemness factors and the nature of the microenvironmental signals that pattern autophagy in different cell types. Here we advance in these directions by reporting that YAP/TAZ transcriptionally control autophagy, being critical for autophagosomal degradation into autolysosomes. YAP/TAZ are downstream effectors of cellular mechanotransduction and indeed we found that cell mechanics, dictated by the physical property of the ECM and cytoskeletal tension, profoundly impact on autophagic flux in a YAP/TAZ-mediated manner. Functionally, by using pancreatic and mammary organoid cultures, we found that YAP/TAZ-regulated autophagy is essential in normal cells for YAP/TAZ-mediated dedifferentiation and acquisition of self-renewing properties. In tumor cells, the YAP/TAZ-autophagy connection is key to sustain transformed traits and for acquisition of a cancer stem cell state by otherwise more benign cells. Mechanistically, YAP/TAZ promote autophagic flux by directly promoting the expression of Armus, a RAB7-GAP required for autophagosome turnover and whose add-back rescues autophagy in YAP/TAZ-depleted cells. These findings expand the influence of YAP/TAZ mechanotransduction to the control of autophagy and, vice versa, the role of autophagy in YAP/TAZ biology, and suggest a mechanism to coordinate transcriptional rewiring with cytoplasmic restructuring during cell reprogramming.
doi: https://doi.org/10.1073/pnas.1908228116
- The applications of metabolomics in the molecular diagnostics of cancer
Expert review of molecular diagnostics 2019 Aug;():1-9
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31414918
Introduction: Metabolomics, the study of metabolites, is a promising research field for cancers. The metabolic pathway in a tumor cell is different from a normal tissue cell. There are two approaches to study the metabolism, targeted and untargeted. The general approach is that metabolomic data are interpreted by bioinformatics tools correlating with metabolomic databases to obtain significant findings. With the use of specific analysis tools, such as nuclear magnetic resonance (NMR) and mass spectrometer (MS) combined with chromatography, metabolic profile or metabolic fingerprint of various biological specimens could be obtained. The applications of metabolomics are used to discover potential cancer biomarkers and monitor the metastatic state, therapeutic and drug response for better patient management. Areas covered: In this review, the author introduce metabolomics and discuss the use of metabolomics approaches in different cancers, including the study of colorectal cancer, prostate cancer, liver cancer, pancreatic cancer and breast cancer using NMR and MS. Expert opinion: Knowledge on the molecular basis of cancer metabolism and its potential clinical applications has been improving recently. However, there are still many challenges for the technological development and integration of metabolomics with other omics spaces such as genomics. In the near future, it is expected that metabolomics will play an important role in cancer molecular diagnostics.
doi: https://doi.org/10.1080/14737159.2019.1656530
- Inflammation Promotes Progression of Pancreatic Cancer Through WNT/β-Catenin Pathway-Dependent Manner
Pancreas 2019 Sep;48(8):1003-1014
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404031
OBJECTIVE: Identify the molecular mechanism of inflammatory stimuli induced pancreatic cancer progression. METHODS: RNA-seq, microarray assay and bioinformatics analyses were used to identify differentially expressed genes. Immunohistochemical staining was performed to evaluate CD68, CD163, β-catenin, CD103, CCL3 markers. Quantitative real-time polymerase chain reaction (qRT-PCR), luciferase reporter assay, apoptosis assay, wound healing assay and immunofluorescence were performed to study the relationship of inflammatory stimuli and WNT/β-catenin pathway. RESULTS: Differentially expressed genes of macrophage-conditioned medium-treated pancreatic cancer cells were related with WNT/β-catenin pathway. Inflammatory stimuli could activate WNT/β-catenin signaling pathway. In 106 pancreatic cancer patients, nuclear β-catenin expression of CD68-high group was much higher than CD68-low group (P < 0.05), as same as CD163 (P < 0.05). Inflammatory stimuli downregulated the expression of CCL3 via WNT/β-catenin pathway and inhibited the chemotaxis of CD103 dendritic cells. Six pancreatic cancer prognosis associating genes were upregulated by inflammatory stimuli via WNT/β-catenin pathway. Transforming growth factor-β promoted malignant biological behavior of pancreatic cancer cells through WNT/β-catenin pathway-dependent mechanism. CONCLUSIONS: Our present study provided a novel mechanism involved in the inflammation-driven cancer progression through tumor immune escape and downstream gene regulation of WNT/β-catenin pathway-dependent manner.
doi: https://doi.org/10.1097/MPA.0000000000001386
- Detection of Reg3γ by Immunohistochemistry in Cerulein-Induced Model of Acute Pancreatic Injury in Mice and Rats
Pancreas 2019 Sep;48(8):1015-1025
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404030
OBJECTIVE: In a continuation of previous work, Reg3γ protein was further evaluated as a biomarker of pancreatic injury using immunohistochemistry in an additional species. METHODS: Mice and rats were treated with intraperitoneal cerulein injections, creating acute pancreatic injury. Mice received 2, 4, or 6 doses, and rats received 1, 2, or 3 doses of cerulein creating low, medium, and high treatment groups. Control animals were dosed with phosphate-buffered saline at corresponding volumes and intervals. Groups of 6 animals were killed 1, 3, 6, 24, and 48 hours after final treatments. Reg3γ immunohistochemical staining and image analysis were performed on pancreatic tissue obtained 6, 24, or 48 hours after control or cerulein treatment. Staining was quantified using image analysis software to calculate area of positivity as a percentage of total tissue area. RESULTS: Percent positivity of Reg3γ in both species rose by 6 hours, peaked by 24 hours across all 3 cerulein doses, and dropped significantly by 48 hours. In high-dose rats with accompanying gene expression data, Reg3γ gene expression corresponded temporally with quantitative staining data. CONCLUSIONS: Reg3γ staining quantified through image analysis showed a time- and dose-response in cerulein-treated mice and rats.
doi: https://doi.org/10.1097/MPA.0000000000001382
- Pancreatic Function in Chronic Pancreatitis: A Cohort Study Comparing 3 Methods of Detecting Fat Malabsorption and the Impact of Short-term Pancreatic Enzyme Replacement Therapy
Pancreas 2019 Sep;48(8):1068-1078
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404029
OBJECTIVES: Reliable pancreatic function tests in patients with chronic pancreatitis (CP) are needed. This cohort study identified malabsorption in people with CP compared with healthy people and then investigated short-term pancreatic enzyme replacement therapy (PERT) and fat malabsorption, nutritional status, and quality of life (QOL). METHODS: Subjects with CP were evaluated before and after PERT and compared with the healthy cohort using coefficient of fat absorption (CFA), stool bomb calorimetry, and the malabsorption blood test (MBT). Anthropometrics, micronutrients, and QOL data were collected. Group means at baseline and after PERT were analyzed. RESULTS: The 24 subjects with CP had greater stool energy loss (5668 cal/g [standard deviation {SD}, 753] vs 5152 cal/g [SD, 418], P < 0.01), reduced triglyceride absorption (MBT, 8.3 mg·h/dL [SD, 4.3] vs 17.7 mg·h/dL [SD, 10.3], P < 0.001), lower fat intake, and poorer QOL. Differences in CFA were not significant (90.9% [SD, 12.8] vs 95.4% [SD, 9.3]). After PERT, triglyceride absorption (Δ = 1.7 [SD, 3], P < 0.05) and QOL increased. CONCLUSIONS: The MBT detected changes in triglyceride absorption in the absence of CFA changes. The MBT may be helpful in guiding PERT initiation in patients with CP before significant morbidity.
doi: https://doi.org/10.1097/MPA.0000000000001381
- Risk and Outcomes of Clostridium difficile Infection With Chronic Pancreatitis
Pancreas 2019 Sep;48(8):1041-1049
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404028
OBJECTIVES: Chronic pancreatitis (CP) is associated with high rates of recurrent hospitalizations, which predisposes to Clostridium difficile infection (CDI). We investigate the burden of CDI in CP. METHODS: We identified records of patients with CP from the Nationwide Inpatient Sample (NIS) 2012-2014 and estimated the impact of CDI on their outcomes. We calculated the adjusted odds ratio (AOR) of CP on having CDI (NIS 2014). From NIS 2007-2014, we plotted the trends of CDI and its interaction with CP. RESULTS: From 2012 to 2014, 886 (2.72%) of the 32,614 CP patients had concomitant CDI, which was associated with poorer outcomes: acute kidney injury (AOR, 2.57 [95% confidence interval {CI}, 2.11-3.13]), length of stay (13.3 vs 7.4 days), and charges (US $127,496 vs US $72,767), but not mortality (AOR, 0.93 [95% CI, 0.28-3.05]). In 2014, CP was associated with an increased risk of CDI (crude odds ratio, 2.10 [95% CI, 1.95-2.26]), which persisted after multivariate adjustment (AOR, 2.03 [95% CI, 1.87-2.19]). From 2007 to 2014, the annual prevalence of CDI was 106.4 cases per 10,000 hospitalizations, increasing from 2007 (95.5/10,000) to 2014 (118.4/10,000), with a 3.7 times higher annual rate of increase among CP versus no-CP patients (13.4/10,000 vs 3.7/10,000 population/year). CONCLUSIONS: Chronic pancreatitis patients have high burden of CDI and may benefit from CDI prophylaxis.
doi: https://doi.org/10.1097/MPA.0000000000001380
- Microbial Contamination, Infection, and Antimicrobial Use During Total Pancreatectomy With Islet Autotransplantation
Pancreas 2019 Sep;48(8):1050-1055
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404027
OBJECTIVES: Total pancreatectomy with islet autotransplantation can relieve pain associated with chronic pancreatitis while preserving islet function. Islet preparations are often contaminated by enteric flora. We assessed the impact of contaminated islet preparations on the prevalence of postoperative infection. METHODS: Electronic health records for patients who underwent total pancreatectomy with islet autotransplantation from August 1, 2011, to November 15, 2017 were retrospectively reviewed to compare the prevalence of postoperative infection in patients with a positive islet culture and islet culture negative patients. RESULTS: Sixty-one patients were included. Twenty-nine patients (47.5%) had a positive islet culture, and 23 (79.3%) of these patients received antimicrobial prophylaxis. The prevalence of postoperative infection did not differ between the islet culture positive and islet culture negative groups (41% vs 34%, P = 0.57). No infections occurred in the 6 islet culture positive patients who did not receive prophylaxis. No difference in intensive care unit or hospital length of stay or in 30-day or 90-day readmission rates were observed. CONCLUSIONS: Despite the common use of postoperative systemic antimicrobials, we observed no difference in the prevalence of postoperative infection, length of stay, or hospital readmission in patients receiving a contaminated islet preparation. If prophylactic antimicrobials are used, the duration should be minimized.
doi: https://doi.org/10.1097/MPA.0000000000001378
- Association Between Pancreatic Cystic Lesions and High-grade Intraepithelial Neoplasia and Aging: An Autopsy Study
Pancreas 2019 Sep;48(8):1079-1085
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404026
OBJECTIVES: This study aimed to clarify clinicopathological features of pancreatic cysts. METHODS: Pancreata from 280 autopsies (median, 83 years; male, 146; female, 134) were sectioned every 5 mm. Cysts (<10 mm) were diagnosed as a simple cyst or low-grade, intermediate-grade, or high-grade dysplasia. RESULTS: We found 236 cysts in 93 patients (33.2%). The number and diameter of cysts increased according to the age. Of the 236 cysts, 9 (3.8%) were with high-grade dysplasia. Cysts with high-grade dysplasia arose in the pancreata of older patients with larger numbers of cysts. In contrast, 15 noncystic lesions with high-grade dysplasia were also detected. Hence, in total, 24 high-grade dysplastic lesions in 15 patients (5.4%) were noted. Of the 15 patients with high-grade dysplastic lesions, in 10 patients, the condition was accompanied by pancreatic cysts, whereas 5 patients did not have any cysts in the pancreas; therefore, patients with cyst showed higher incidence of high-grade dysplasia (10.8%; P = 0.0047) than patients without cyst (2.7%). All cysts with high-grade dysplasia were located in the branch duct of the pancreatic head/body, whereas 20% of noncystic lesions with high-grade dysplasia were located in the main pancreatic duct. CONCLUSIONS: Cystic lesions with high-grade dysplasia may have different characteristics compared with noncystic high-grade dysplasia.
doi: https://doi.org/10.1097/MPA.0000000000001374
- 18F-Fluorodeoxyglucose Positron Emission Tomography Predicts Treatment Efficacy and Clinical Outcome for Patients With Pancreatic Carcinoma: A Meta-analysis
Pancreas 2019 Sep;48(8):996-1002
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404025
OBJECTIVES: F-Fluorodeoxyglucose positron emission tomography (FDG-PET) has been an important modality for detecting malignancies. Recently, an increasing number of studies reported the utility of FDG-PET parameters in predicting clinical outcomes and treatment assessment in variety of cancers. We aimed at clarifying both the prognostic role and assessment value of FDG-PET in pancreatic carcinoma. METHODS: We systematically searched electronic databases of PubMed, Embase, Cochrane Library, and Web of Science to identify relevant studies to conduct this meta-analysis. Comparative analyses of the pooled hazard ratio (HR) for overall survival were performed to assess the utility of FDG-PET parameters in prognosis evaluation and treatment assessment by random-effect model. RESULTS: Twenty-three studies with 1762 patients met the inclusion criteria of this meta-analysis. The pooled results revealed that greater maximum standardized uptake value of the primary tumor was significantly correlated with poorer overall survival (HR, 1.31; 95% confidence interval, 1.15-1.50; P < 0.001). Besides, greater reduction of maximum standardized uptake value after treatments indicated significant better overall survival (HR, 0.68; 95% confidence interval, 0.47-0.98; P = 0.037). CONCLUSIONS: F-Fluorodeoxyglucose positron emission tomography parameters might be helpful not only for predicting survival outcome but also for selecting potentially efficacious treatments in patients with pancreatic carcinoma.
doi: https://doi.org/10.1097/MPA.0000000000001375
- Time to Adjuvant Systemic Therapy Following Pancreatic Cancer Resection and Effect on Outcome
Pancreas 2019 Sep;48(8):1086-1091
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404024
OBJECTIVES: The appropriate timing of chemotherapy following surgery for resectable pancreatic adenocarcinoma is controversial. Using the National Cancer Database we evaluated time to initiation of chemotherapy postresection and correlated with outcome. METHODS: We identified stage I-III pancreatic adenocarcinoma treated surgically with adjuvant chemoradiotherapy. Receiver operator curve analysis identified an interval of 66 days as the a priori value for largest discrepancy in outcome. Multivariable logistic regression analysis identified variables associated with increased time to chemotherapy postoperatively (>66 days). Propensity matching was performed to account for indication bias. RESULTS: In total, 6873 and 3348 patients received chemotherapy before and after the 66-day cutoff, respectively. Predictors of expedited chemotherapy included lower comorbidity, treatment outside a community program in an urban location, having insurance, white race, and treatment after 2009. Propensity-matched median survival was 21.8 months for all patients, and of these, 6462 were stage 1. Five-year survival was 20% in patients receiving chemotherapy within 66 days and 18% in those not (P = 0.0266). In stage 1 patients, 5-year survival was 23% versus 21% (P = 0.0116) in favor of expedited chemotherapy. CONCLUSIONS: The present propensity-matched analysis showed a significant association with survival for earlier delivery of chemotherapy in the adjuvant setting.
doi: https://doi.org/10.1097/MPA.0000000000001373
- Pancreatic Fluid Interleukin-1β Complements Prostaglandin E2 and Serum Carbohydrate Antigen 19-9 in Prediction of Intraductal Papillary Mucinous Neoplasm Dysplasia
Pancreas 2019 Sep;48(8):1026-1031
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404023
OBJECTIVES: We sought to determine if interleukin (IL)-1β and prostaglandin E2 (PGE2) (inflammatory mediators in pancreatic fluid) together with serum carbohydrate antigen (CA) 19-9 could better predict intraductal papillary mucinous neoplasm (IPMN) dysplasia than individual biomarkers alone. METHODS: Pancreatic cyst fluid (n = 92) collected via endoscopy or surgery (2003-2016) was analyzed for PGE2 and IL-1β (enzyme-linked immunosorbent assay). Patients had surgical pathology-proven IPMN. Threshold values (PGE2 [>1100 pg/mL], IL-1β [>20 pg/mL], and serum CA 19-9 [>36 U/mL]) were determined. RESULTS: Levels of IL-1β were higher in high-grade dysplasia (HGD)/invasive-IPMN (n = 42) compared with low/moderate IPMN (n = 37) (median [range], 54.6 [0-2671] vs 5.9 [0-797] pg/mL; P < 0.001; area under curve [AUC], 0.766). Similarly, PGE2 was higher in HGD/invasive IPMN (n = 45) compared with low/moderate IPMN (n = 47) (median [range], 1790 [20-15,180] vs. 140 [10-14,630] pg/mL; P < 0.001; AUC, 0.748). Presence of elevated PGE2 and IL-1β (AUC, 0.789) provided 89% specificity and 82% positive predictive value (PPV) for HGD/invasive IPMN. Elevated levels of all 3 provided 100% specificity and PPV for HGD/invasive IPMN. CONCLUSIONS: Cyst fluid PGE2, IL-1β, and serum CA 19-9 in combination optimize specificity and PPV for HGD/invasive IPMN and may help build a panel of markers to predict IPMN dysplasia.
doi: https://doi.org/10.1097/MPA.0000000000001377
- Etiologic Distribution of Pancreatic Cystic Lesions Identified on Computed Tomography/Magnetic Resonance Imaging
Pancreas 2019 Sep;48(8):1092-1097
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404022
OBJECTIVES: This study aimed to determine the distribution of etiology of pancreatic cysts using established criteria/markers from cyst fluid analysis and cytology that have been reported to have high specificity in published literature. METHODS: A retrospective study of pancreatic cysts using an endoscopic database from March 2002 and May 2013 was conducted. Pancreatic cysts <10 mm and cysts with a history of pancreatic cancer were excluded. RESULTS: In our cohort of 758 patients with pancreatic cyst(s), the cyst etiology was as follows: mucinous cyst/side-branch intraductal papillary mucinous neoplasms (SB-IPMNs)/mucinous cystic neoplasms (MCN; 48.2%), pseudocyst (27.6%), serous cystadenoma (11%), simple cysts (6.4%), mucinous cystadenocarcinoma (5.1%), and other (1%). Approximately 41% (n = 310) of the cysts were ≥3 cm in size and included the following: pseudocyst (39.7%), mucinous cysts/SB-IPMN/MCN (28.1%), serous cystadenoma (16.7%), mucinous cyst adenocarcinoma (9.7%), and simple cyst (4.8%). In 118 patients with a known history of acute pancreatitis, the cyst diagnoses included pseudocyst (68.7%), mucinous cyst/SB-IPMN/MCN (18.6%), benign/simple cyst (7.6%), and mucinous cystadenocarcinoma (2.5%). CONCLUSIONS: In patients with cystic pancreatic lesion noted on cross-sectional imaging, approximately half of the patients have lesions without malignancy or malignant potential and therefore not requiring surveillance. Endoscopic ultrasound/endoscopic ultrasound-guided fine-needle aspiration evaluation of the pancreatic cysts can help optimize their further management.
doi: https://doi.org/10.1097/MPA.0000000000001372
- Mutational Patterns in Pancreatic Juice of Intraductal Papillary Mucinous Neoplasms and Concomitant Pancreatic Cancer
Pancreas 2019 Sep;48(8):1032-1040
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404021
OBJECTIVES: The aims of this study were to identify genetic characteristics of intraductal papillary mucinous neoplasm (IPMN)-associated pancreatic ductal carcinoma (PDC) and to detect these markers using pancreatic juice. METHODS: From 76 cases, 102 tissues were obtained: 29 cases were noninvasive IPMN, 18 were PDC derived from IPMN (D-PDC; noninvasive part, n = 16; invasive part, n = 18), and 29 were PDC concomitant with IPMN (C-PDC; IPMN part, n = 10; PDC part, n = 29). Moreover, pancreatic juice samples from 28 cases were obtained (noninvasive IPMN, n = 13; D-PDC, n = 7; C-PDC, n = 8). Fifty-one cancer-related genes were analyzed by next-generation sequencing. RESULTS: TP53 mutation rates in D-PDC, C-PDC, and noninvasive IPMN were 67%, 66%, and 10%, respectively. Moreover, KRAS mutational patterns between 2 simultaneous tumors differed in 1 (6.3%) of the 16 D-PDC cases and in 8 (80%) of the 10 C-PDC cases (P = 0.0006). TP53 or multiple KRAS mutations were detected using pancreatic juice more frequently in C-PDC cases than in noninvasive IPMN cases (75% and 23%, respectively, P = 0.03). CONCLUSIONS: Multiple KRAS mutations along with TP53 mutation are genetic markers for C-PDC, which could be detected using pancreatic juice preoperatively.
doi: https://doi.org/10.1097/MPA.0000000000001371
- SpHincterotomy for Acute Recurrent Pancreatitis Randomized Trial: Rationale, Methodology, and Potential Implications
Pancreas 2019 Sep;48(8):1061-1067
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404020
OBJECTIVES: In patients with acute recurrent pancreatitis (ARP), pancreas divisum, and no other etiologic factors, endoscopic retrograde cholangiopancreatography (ERCP) with minor papilla endoscopic sphincterotomy (miES) is often performed to enlarge the minor papillary orifice, based on limited data. The aims of this study are to describe the rationale and methodology of a sham-controlled clinical trial designed to test the hypothesis that miES reduces the risk of acute pancreatitis. METHODS: The SpHincterotomy for Acute Recurrent Pancreatitis (SHARP) trial is a multicenter, international, sham-controlled, randomized trial comparing endoscopic ultrasound + ERCP with miES versus endoscopic ultrasound + sham for the management of ARP. A total of 234 consented patients having 2 or more discrete episodes of acute pancreatitis, pancreas divisum confirmed by magnetic resonance cholangiopancreatography, and no other clear etiology for acute pancreatitis will be randomized. Both cohorts will be followed for a minimum of 6 months and a maximum of 48 months. RESULTS: The trial is powered to detect a 33% risk reduction of acute pancreatitis frequency. CONCLUSIONS: The SHARP trial will determine whether ERCP with miES benefits patients with idiopathic ARP and pancreas divisum. Trial planning has informed the importance of blinded outcome assessors and long-term follow-up.
doi: https://doi.org/10.1097/MPA.0000000000001370
- Expression of Monocarboxylate Transporter 1 Is Associated With Better Prognosis and Reduced Nodal Metastasis in Pancreatic Ductal Adenocarcinoma
Pancreas 2019 Sep;48(8):1102-1110
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404019
OBJECTIVES: Because lactate is believed to support tumor growth, monocarboxylate transporters (MCTs), which transport lactate, have been investigated in multiple tumors. However, the significance of MCTs in pancreatic cancer is unclear. METHODS: A retrospective survey was conducted on 240 patients who underwent surgical resection for pancreatic ductal adenocarcinoma without preoperative treatment. The expression of MCT1, MCT2, MCT3, MCT4, and the glucose transporter 1 (GLUT1) was assessed in tumor cells and cancer-associated fibroblasts (CAFs) by tissue microarrays and immunohistochemistry. The impact of their expression on patient outcome and clinicopathological characteristics was also analyzed. RESULTS: In tumor cells, MCT1, MCT2, MCT3, MCT4, and GLUT1 were detected in 52 (22%), 31 (13%), 149 (62%), 204 (85%), and 235 (98%) cases, respectively. In CAFs, MCT2, MCT4, and GLUT1 were detected in 9 (3.8%), 178 (74%), and 36 (15%) cases, respectively. In tumor cells, MCT1 expression was associated with extended overall and progression-free survival and decreased nodal metastasis. Conversely, MCT4 expression in CAFs was associated with shortened survival. CONCLUSIONS: In tumor cells, MCT1 expression is associated with better prognosis and reduced nodal metastasis in pancreatic cancer, contrary to findings of past in vitro studies. Conversely, MCT4 expression in CAFs is indicative of worse prognosis.
doi: https://doi.org/10.1097/MPA.0000000000001369
- Prevention of Infectious Complications in Acute Pancreatitis: Results of a Single-Center, Randomized, Controlled Trial
Pancreas 2019 Sep;48(8):1056-1060
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404018
OBJECTIVES: This study aimed to investigate the efficiency of imipenem to prevent infectious complications in predicted severe acute pancreatitis (AP). METHODS: Consecutive AP patients were randomized to imipenem 3 × 500 mg intravenously daily or an identical placebo. Exclusion criteria were prior AP, chronic pancreatitis, active malignancy, immune deficiency, active infection, concomitant antibiotic treatment, pregnancy, and patients younger than 18 years. Infectious complications including infected pancreatic necrosis, pneumonia, urinary tract infection, positive blood cultures, sepsis, and other infections were assessed as the primary outcome. Secondary outcomes included mortality, persistent organ failure, systemic inflammatory response syndrome, local complications, serious adverse events, and need for surgical intervention. RESULTS: Forty-nine patients were randomized to each group. Infectious complications were present in 10 versus 12 of 49 patients (relative risk [RR], 0.833; 95% confidence interval [CI], 0.398-1.747). There were no significant differences in infected pancreatic necrosis (RR, 1.5; 95% CI, 0.262-8.588), pneumonia (RR, 1.5; 95% CI, 0.262-8.588), urinary tract infection (RR, 0.6; 95% CI, 0.152-2.374), positive blood cultures (RR, 0.5; 95% CI, 0.047-5.336), sepsis (RR, 0.333; 95% CI, 0.036-3.095), and other (RR, 1.333; 95% CI, 0.315-5.648). We found no significant differences in secondary outcomes. CONCLUSIONS: Concordantly to available evidence, there is currently no ground to support prophylactic use of antibiotics in predicted severe AP.
doi: https://doi.org/10.1097/MPA.0000000000001368
- Defining Pancreatitis as a Risk Factor for Pancreatic Cancer: The Role, Incidence, and Timeline of Development
Pancreas 2019 Sep;48(8):1098-1101
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404017
OBJECTIVES: Acute and/or chronic pancreatitis has been implicated as an important risk factor for pancreatic cancer; however, the incidence and temporal relationship of pancreatitis before pancreatic cancer diagnosis are unclear. We aim to understand the role and incidence of pancreatitis temporally with the development of pancreatic cancer. METHODS: A population-based study was used to investigate a temporal relationship between pancreatitis and pancreatic cancer diagnoses. Intervals of 3, 6, 12, 24, and 36 months were developed. Demographical data including age, sex, and race were also recorded and analyzed. RESULTS: A total of 50,080 patients were found to have a diagnosis of pancreatic cancer, of which 7420 (14.8%) had prior diagnoses of pancreatitis. Of those, 92% were between the ages of 40 and 89 years. African Americans had a higher rate of pancreatitis before cancer diagnosis when compared with whites (21.2% vs 14.8%, P < 0.0001). Further analysis revealed that pancreatitis occurred in 81.3% of patients 3 months before a diagnosis of pancreas cancer and 98.9% had established diagnoses of pancreatic cancer within 3 years. CONCLUSIONS: Screening of patients older than 40 years who have pancreatitis and unclear etiology of pancreatitis may be warranted, especially in African Americans and male individuals.
doi: https://doi.org/10.1097/MPA.0000000000001367
- ARF6 and AMAP1 are major targets of KRAS and TP53 mutations to promote invasion, PD-L1 dynamics, and immune evasion of pancreatic cancer
Proceedings of the National Academy of Sciences of the United States of America 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31399545
Although KRAS and TP53 mutations are major drivers of pancreatic ductal adenocarcinoma (PDAC), the incurable nature of this cancer still remains largely elusive. ARF6 and its effector AMAP1 are often overexpressed in different cancers and regulate the intracellular dynamics of integrins and E-cadherin, thus promoting tumor invasion and metastasis when ARF6 is activated. Here we show that the ARF6-AMAP1 pathway is a major target by which KRAS and TP53 cooperatively promote malignancy. KRAS was identified to promote eIF4A-dependent ARF6 mRNA translation, which contains a quadruplex structure at its 5’-untranslated region, by inducing TEAD3 and ETV4 to suppress PDCD4; and also eIF4E-dependent AMAP1 mRNA translation, which contains a 5’-terminal oligopyrimidine-like sequence, via up-regulating mTORC1. TP53 facilitated ARF6 activation by platelet-derived growth factor (PDGF), via its known function to promote the expression of PDGF receptor β (PDGFRβ) and enzymes of the mevalonate pathway (MVP). The ARF6-AMAP1 pathway was moreover essential for PDGF-driven recycling of PD-L1, in which KRAS, TP53, eIF4A/4E-dependent translation, mTOR, and MVP were all integral. We moreover demonstrated that the mouse PDAC model KPC cells, bearing KRAS/TP53 mutations, express ARF6 and AMAP1 at high levels and that the ARF6-based pathway is closely associated with immune evasion of KPC cells. Expression of ARF6 pathway components statistically correlated with poor patient outcomes. Thus, the cooperation among eIF4A/4E-dependent mRNA translation and MVP has emerged as a link by which pancreatic driver mutations may promote tumor cell motility, PD-L1 dynamics, and immune evasion, via empowering the ARF6-based pathway and its activation by external ligands.
doi: https://doi.org/10.1073/pnas.1901765116
- Second harmonic generation detection of Ras conformational changes and discovery of a small molecule binder
Proceedings of the National Academy of Sciences of the United States of America 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31399543
Second harmonic generation (SHG) is an emergent biophysical method that sensitively measures real-time conformational change of biomolecules in the presence of biological ligands and small molecules. This study describes the successful implementation of SHG as a primary screening platform to identify fragment ligands to oncogenic Kirsten rat sarcoma (KRas). KRas is the most frequently mutated driver of pancreatic, colon, and lung cancers; however, there are few well-characterized small molecule ligands due to a lack of deep binding pockets. Using SHG, we identified a fragment binder to KRasG12D and used 1H 15N transverse relaxation optimized spectroscopy (TROSY) heteronuclear single-quantum coherence (HSQC) NMR to characterize its binding site as a pocket adjacent to the switch 2 region. The unique sensitivity of SHG furthered our study by revealing distinct conformations induced by our hit fragment compared with 4,6-dichloro-2-methyl-3-aminoethyl-indole (DCAI), a Ras ligand previously described to bind the same pocket. This study highlights SHG as a high-throughput screening platform that reveals structural insights in addition to ligand binding.
doi: https://doi.org/10.1073/pnas.1905516116
- The harms of early cessation of trials on systematic reviews - Authors’ reply
The lancet. Gastroenterology & hepatology 2019 Sep;4(9):667-668
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31387729
doi: https://doi.org/10.1016/S2468-1253(19)30228-6
- Silibinin inhibited autophagy and mitochondrial apoptosis in pancreatic carcinoma by activating JNK/SAPK signaling
Pathology, research and practice 2019 Sep;215(9):152530
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31351801
BACKGROUND: Previous investigation have indicated Silibinin induces apoptosis and JNK/SAPK in human pancreatic cancer cells. This study aims to evaluate the further mechanism of Silibinin in pancreatic cancer treatment. MATERIALS AND METHODS: Human pancreatic cancer cell lines SW1990 was treated with Silibinin and/or JNK/SAPK inhibitor SP600125 followed by measurement of cell viability, apoptosis, autophagy, ROS and ATP, and western blotting. RESULTS: Silibinin promoted cell viability and promoted cell apoptosis. The expression of ROS and ATP associated with mitochondrial function was also promoted by the treatment of silibinin. Silibinin also promoted autophagy in pancreatic cancer cells. All these biological effects of Silibinin can be reversed by JNK/SAPK inhibitor. CONCLUSIONS: The biological effects regulated by Silibinin can be mediated by JNK/SAPK signaling. This provides a solid theoretical basis for the role of Silibinin in the treatment of pancreatic cancer.
doi: https://doi.org/10.1016/j.prp.2019.152530
- Tumor Budding in Intrahepatic Cholangiocarcinoma: A Predictor of Postsurgery Outcomes
The American journal of surgical pathology 2019 Sep;43(9):1180-1190
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31335353
Intrahepatic cholangiocarcinoma (ICC) is an extremely aggressive carcinoma. Useful predictors for the patients’ prognosis after surgery have not been fully established. From the University of Tokyo Hospital pathology archives, we reviewed 107 cases of ICC, 54 cases of perihilar cholangiocarcinoma, and 40 cases of extrahepatic cholangiocarcinoma (ECC); we also investigated the significance of tumor budding in ICC, in comparison with perihilar cholangiocarcinoma and ECC. The tumor-budding frequencies were different by tumor location: 40.2% (43/107) in ICC, 70.4% (38/54) in perihilar cholangiocarcinoma, and 60.0% (24/40) in ECC. Tumor budding in ICC was associated with many pathologic indicators associated with invasion, such as major vascular invasion (P=0.012) and Union for International Cancer Control stage (P=0.007). Univariate and multivariate Cox regression analyses revealed tumor budding as a powerful prognostic factor for both recurrence-free survival (RFS) and overall survival (OS) in ICC by univariate (RFS: hazard ratio [HR]: 2.666; 95% confidence interval [CI]: 1.517-4.683, OS: HR: 4.206; 95% CI: 2.447-7.230) and by multivariate analyses (RFS: HR: 3.038; 95% CI: 1.591-5.973, OS: HR: 4.547, 95% CI: 2.348-8.805). Tumor budding was also a significant prognostic factor of perihilar cholangiocarcinoma, but not of ECC. When ICC was divided into 2 subtypes, type 1 (hilar) and type 2 (peripheral), tumor budding was the strong prognostic factor in type 2 ICC, but not in type 1 ICC, suggesting that some differences in biological behavior exist between type 1 ICC and perihilar cholangiocarcinoma. Tumor budding is prognostically important in ICC, and its pathogenetic role in biliary tract carcinomas might be different by anatomic location.
doi: https://doi.org/10.1097/PAS.0000000000001332
- Vaccination for Pancreatic Ductal Adenocarcinoma: A Hard Nut to Crack
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Sep;25(18):5435-5437
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31315885
No immunotherapy strategy is yet offering consistent results against pancreatic ductal adenocarcinoma. A randomized clinical trial testing repeated immunization with a Listeria monocytogenes-based vaccine encoding for mesothelin in combination with a GM-CSF-transfected allogeneic pancreatic cell vaccine reports no survival benefit for the vaccinated patients.See related article by Le et al., p. 5493.
doi: https://doi.org/10.1158/1078-0432.CCR-19-1753
- Novel Methylated DNA Markers Discriminate Advanced Neoplasia in Pancreatic Cysts: Marker Discovery, Tissue Validation, and Cyst Fluid Testing
The American journal of gastroenterology 2019 Sep;114(9):1539-1549
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31306149
OBJECTIVES: Pancreatic cystic lesions (PCLs) may be precancerous. Those likely to harbor high-grade dysplasia (HGD) or pancreatic cancer (PC) are targets for surgical resection. Current algorithms to predict advanced neoplasia (HGD/PC) in PCLs lack diagnostic accuracy. In pancreatic tissue and cyst fluid (CF) from PCLs, we sought to identify and validate novel methylated DNA markers (MDMs) that discriminate HGD/PC from low-grade dysplasia (LGD) or no dysplasia (ND). METHODS: From an unbiased whole-methylome discovery approach using predefined selection criteria followed by multistep validation on case (HGD or PC) and control (ND or LGD) tissues, we identified discriminant MDMs. Top candidate MDMs were then assayed by quantitative methylation-specific polymerase chain reaction on archival CF from surgically resected PCLs. RESULTS: Of 25 discriminant MDMs identified in tissue, 13 were selected for validation in 134 CF samples (21 cases [8 HGD, 13 PC], 113 controls [45 ND, 68 LGD]). A tree-based algorithm using 2 CF-MDMs (TBX15, BMP3) achieved sensitivity and specificity above 90%. Discrimination was significantly better by this CF-MDM panel than by mutant KRAS or carcinoembryonic antigen, with areas under the receiver operating characteristic curve of 0.93 (95% confidence interval: 0.86-0.99), 0.71 (0.57-0.85), and 0.72 (0.60-0.84), respectively. Cutoffs for the MDM panel applied to an independent CF validation set (31 cases, 56 controls) yielded similarly high discrimination, areas under the receiver operating characteristic curve = 0.86 (95% confidence interval: 0.77-0.94, P = 0.2). DISCUSSION: Novel MDMs discovered and validated in tissue accurately identify PCLs harboring HGD/PC. A panel of 2 MDMs assayed in CF yielded results with potential to enhance current risk prediction algorithms. Prospective studies are indicated to optimize and further evaluate CF-MDMs for clinical use.
doi: https://doi.org/10.14309/ajg.0000000000000284
- Survival Outcomes Associated With Clinical and Pathological Response Following Neoadjuvant FOLFIRINOX or Gemcitabine/Nab-Paclitaxel Chemotherapy in Resected Pancreatic Cancer
Annals of surgery 2019 Sep;270(3):400-413
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31283563
OBJECTIVE: To compare the survival outcomes associated with clinical and pathological response in pancreatic ductal adenocarcinoma (PDAC) patients receiving neoadjuvant chemotherapy (NAC) with FOLFIRINOX (FLX) or gemcitabine/nab-paclitaxel (GNP) followed by curative-intent pancreatectomy. BACKGROUND: Newer multiagent NAC regimens have resulted in improved clinical and pathological responses in PDAC; however, the effects of these responses on survival outcomes remain unknown. METHODS: Clinicopathological and survival data of PDAC patients treated at 7 academic medical centers were analyzed. Primary outcomes were overall survival (OS), local recurrence-free survival (L-RFS), and metastasis-free survival (MFS) associated with biochemical (CA 19-9 decrease ≥50% vs <50%) and pathological response (complete, pCR; partial, pPR or limited, pLR) following NAC. RESULTS: Of 274 included patients, 46.4% were borderline resectable, 25.5% locally advanced, and 83.2% had pancreatic head/neck tumors. Vein resection was performed in 34.7% and 30-day mortality was 2.2%. R0 and pCR rates were 82.5% and 6%, respectively. Median, 3-year, and 5-year OS were 32 months, 46.3%, and 30.3%, respectively. OS, L-RFS, and MFS were superior in patients with marked biochemical response (CA 19-9 decrease ≥50% vs <50%; OS: 42.3 vs 24.3 months, P < 0.001; L-RFS-27.3 vs 14.1 months, P = 0.042; MFS-29.3 vs 13 months, P = 0.047) and pathological response [pCR vs pPR vs pLR: OS- not reached (NR) vs 40.3 vs 26.1 months, P < 0.001; L-RFS-NR vs 24.5 vs 21.4 months, P = 0.044; MFS-NR vs 23.7 vs 20.2 months, P = 0.017]. There was no difference in L-RFS, MFS, or OS between patients who received FLX or GNP. CONCLUSION: This large, multicenter study shows that improved biochemical, pathological, and clinical responses associated with NAC FLX or GNP result in improved OS, L-RFS, and MFS in PDAC. NAC with FLX or GNP has similar survival outcomes.
doi: https://doi.org/10.1097/SLA.0000000000003468
- A Novel Validated Recurrence Risk Score to Guide a Pragmatic Surveillance Strategy After Resection of Pancreatic Neuroendocrine Tumors: An International Study of 1006 Patients
Annals of surgery 2019 Sep;270(3):422-433
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31283562
OBJECTIVE: Despite heterogeneous biology, similar surveillance schemas are utilized after resection of all pancreatic neuroendocrine tumors (PanNETs). Given concerns regarding excess radiation exposure and financial burden, our aim was to develop a prognostic score for disease recurrence to guide individually tailored surveillance strategies. METHODS: All patients with primary nonfunctioning, nonmetastatic well/moderately differentiated PanNETs who underwent curative-intent resection at 9-institutions from 2000 to 2016 were included (n = 1006). A Recurrence Risk Score (RRS) was developed from a randomly selected derivation cohort comprised of 67% of patients and verified on the validation-cohort comprised of the remaining 33%. RESULTS: On multivariable analysis, patients within the derivation cohort (n = 681) with symptomatic tumors (jaundice, pain, bleeding), tumors >2 cm, Ki67 >3%, and lymph node (LN) (+) disease had increased recurrence. Each factor was assigned a score based on their weighted odds ratio that formed a RRS of 0 to 10: symptomatic = 1, tumor >2 cm = 2, Ki67 3% to 20% = 1, Ki67 >20% = 6, LN (+) = 1. Patients were grouped into low- (RRS = 0-2; n = 247), intermediate-(RRS = 3-5; n = 204), or high (RRS = 6-10; n = 9)-risk groups. At 24 months, 33% of high RRS recurred, whereas only 2% of low and 14% of intermediate RRS recurred. This persisted in the validation cohort (n = 325). CONCLUSIONS: This international, novel, internally validated RRS accurately stratifies recurrence-free survival for patients with resected PanNETs. Given their unique recurrence patterns, surveillance intervals of 12, 6, and 3 months are proposed for low, intermediate, and high RRS patients, respectively, to minimize radiation exposure and optimize cost/resource utilization.
doi: https://doi.org/10.1097/SLA.0000000000003461
- Well-differentiated Pancreatic Neuroendocrine Tumor in a Patient With Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM)
The American journal of surgical pathology 2019 Sep;43(9):1297-1302
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31261289
Germline mutations in CDKN2A result in Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM), which is associated with an increased risk for pancreatic ductal adenocarcinoma and melanoma. CDKN2A is somatically inactivated in multiple neoplasms, raising the possibility that, although the data are not conclusive, germline CDKN2A mutation may also impose an increased risk for other neoplasms. We present a patient with a CDKN2A germline mutation (p16-Leiden mutation) and mosaicism for neurofibromatosis type 2, who presented with a small asymptomatic pancreatic lesion, detected during endoscopic ultrasound screening of the pancreas. After resection, the lesion was found to be a well-differentiated pancreatic neuroendocrine tumor (PanNET). Molecular analysis of the tumor showed somatic loss of the second allele, supporting a causal relation of the PanNET to the underlying FAMMM syndrome. Recent data, showing the association between certain single-nucleotide polymorphisms in the CDKN2A gene and an increased incidence for PanNET, further support a role for germline CDKN2A alterations in PanNET risk. We conclude that PanNETs can be a phenotypic expression of FAMMM syndrome. This can have implications for screening and for the diagnosis of pancreatic neoplasms in carriers of germline CDKN2A mutations.
doi: https://doi.org/10.1097/PAS.0000000000001314
- miR-199a-3p targets ETNK1 to promote invasion and migration in gastric cancer cells and is associated with poor prognosis
Pathology, research and practice 2019 Sep;215(9):152511
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31255331
PURPOSE: To investigate the prognostic significance of miR-199a-3p and its role in invasion and metastasis in gastric cancer. METHODS: miR-199a-3p expression in 436 formalin-fixed and 39 frozen gastric cancer tissues was investigated by in situ hybridization and RT-PCR, respectively. The role of miR-199a-3p in the migration and invasion of gastric cancer cells was determined in overexpression and inhibitor studies using transwell assays and the SGC-7901, BGC-823 and MGC-803 gastric cancer cells lines. The effect of miR-199a-3p expression on ethanolamine kinase 1 (ETNK1) levels was determined by western botting. RESULTS: miR-199a-3p was significantly up-regulated in AGS, SGC-7901, BGC-823 and MGC-803 gastric cancer cells, when compared with GES-1 non-malignant gastric epithelial cells. In situ hybridization studies revealed that human non-tumor gastric mucosa samples were negative for miR-199a-3p expression, while 162 of 436 (37.16%) cases of gastric cancer demonstrated positive expression. miR-199a-3p overexpression was associated with tumor size, Lauren classification, depth of invasion, lymph node and distant metastasis, TNM stage and prognosis. In patients with I, II and III stage tumors, high miR-199a-3p expression was associated with a significantly lower 5-year survival rate. miR-199a-3p overexpression was associated with increased cell migration and invasion. ETNK1 expression was inhibited following miR-199a-3p overexpression in BGC-823 and SGC-7901 cells, and elevated following miR-199a-3p suppression in MGC-803 cells. CONCLUSION: miR-199a-3p is highly expressed in gastric cancer, and correlates with invasion, metastasis and prognosis. miR-199a-3p regulates the invasion and migration of gastric cancer cells by targeting ETNK1. Consequently, miR-199a-3p may serve as a prognostic indicator in gastric cancer.
doi: https://doi.org/10.1016/j.prp.2019.152511
- Cytopathology of anaplastic carcinoma of the pancreas: Review of a rare entity and description of a variant with signet ring cell features
Diagnostic cytopathology 2019 Sep;47(9):956-960
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31254330
Anaplastic carcinoma of the pancreas (ACP) is a rare and aggressive variant of pancreatic ductal adenocarcinoma (PDAC). Several studies have attempted to characterize this subtype through case series or single case reports; however, ACP remains underrecognized by cytopathologists in particular, and often lumped under the umbrella of classic PDAC. Here, we review the most up to date data that literature provides about ACP, to bring familiarity with this entity to the cytopathology practice, and to elucidate the role cytopathologists can play in recognizing and diagnosing this subtype on pancreatic aspiration biopsy, before surgical resection. We also describe a rare case of ACP, demonstrating signet ring cell features, that was diagnosed on fine needle aspiration of a pancreatic mass.
doi: https://doi.org/10.1002/dc.24263
- Of scientists and tweets
Nature reviews. Cancer 2019 Sep;19(9):479-480
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31253855
doi: https://doi.org/10.1038/s41568-019-0170-4
- Cytohistological diagnosis of pancreatic serous cystadenoma: a multimodal approach
Journal of clinical pathology 2019 Sep;72(9):615-621
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31235542
AIMS: Serous cystadenomata (SCAs) are benign pancreatic cystic neoplasms that present a diagnostic challenge despite many investigational approaches. Notwithstanding the promise of molecular diagnostics, these tests have limited accessibility in day-to-day surgical pathology practices. We aim to corroborate and build on recent evidence which suggests that positive α-inhibin immunohistochemistry (IHC) is a helpful adjunct in the biopsy confirmation of pancreatic SCA. METHODS: We retrospectively reviewed 22 fine-needle aspirates/biopsies from 14 patients (mean age 65 years, 47-83 years) with pancreatic multicystic lesions radiologically suspicious for SCA (location: 6 body, 2 head, 4 tail, 1 neck, 1 uncinate; cyst size: mean 3.7 cm, 2.0-7.6 cm), as well as an additional 10 pancreatic resection specimens with confirmed SCA; α-inhibin IHC was performed on all cell blocks, biopsy slides and representative resection specimen sections. Where available, associated cyst fluid was analysed for correlative vascular endothelial growth factor A (VEGF-A) and carcinoembryonic antigen levels. RESULTS: An α-inhibin IHC sensitivity of 80% was observed in the cases with resection confirmed SCA. Of the fine-needle aspirate/biopsy specimens, 59% (13/22) contained epithelial cells strongly positive for α-inhibin. When selecting for specimens that exhibited distinct strips of epithelium, the α-inhibin strong positivity rate increased to 73% (8/11). VEGF-A values were supportive of false-negative α-inhibin IHC in three cases and true-negative α-inhibin IHC in one case. CONCLUSION: This study postulates a diagnostic algorithm to confirm pancreatic SCA which may help to decrease unnecessary follow-up endoscopy/surgical resection and would decrease the associated morbidity, mortality and financial costs in patients with this otherwise benign condition.
doi: https://doi.org/10.1136/jclinpath-2019-205872
- Accurate and Dynamic Monitoring of Pancreatic Endocrine Function Is Required in Discharged Patients With Necrotizing Pancreatitis
Gastroenterology 2019 09;157(3):892
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31228436
doi: https://doi.org/10.1053/j.gastro.2018.12.052
- Quality of Life Following Major Laparoscopic or Open Pancreatic Resection
Annals of surgical oncology 2019 Sep;26(9):2985-2993
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31228131
PURPOSE: This study was designed to compare quality of life (QoL) among patients who underwent open versus laparoscopic pancreatic resection, including distal pancreatectomy and pancreaticoduodenectomy, and to identify clinical characteristics that are associated with changes in QoL. METHODS: Quality of life (QoL) was assessed in patients undergoing pancreatic resection with the Functional Assessment of Cancer Therapy-Hepatobiliary questionnaire preoperatively and 2 weeks, 1, 3, and 6 months postoperatively. Multilevel regression modeling was used to determine the variability in each QoL domain within the first 2 weeks (postoperative period) and thereafter (recovery period). RESULTS: Among 159 patients, 60.4% underwent open and 39.6% underwent laparoscopic surgery. Physical, functional, hepatobiliary, and total QoL scores decreased in the postoperative period but returned to baseline levels by 6 months postoperatively. Emotional QoL improved from baseline by 2 weeks after surgery (p < 0.001) and social QoL improved from baseline by 3 months after surgery (p < 0.001). Emotional QoL was the only domain where significant differences were observed in QoL in the postoperative and recovery periods between patients who underwent open and laparoscopic pancreatic resection. Controlling for surgical approach, patients who experienced a grade III or IV complication experienced greater declines in physical, functional, hepatobiliary, and total QoL in the postoperative period. The negative impact of complications on QoL resolved by 6 months postoperatively. CONCLUSIONS: The impact of pancreatic resection on QoL was comparable between patients who underwent laparoscopic versus open pancreatic resection. Complications were strongly associated with changes in postoperative QoL, suggesting that performing a safe operation is the best approach for optimizing patient reported QoL.
doi: https://doi.org/10.1245/s10434-019-07449-x
- Outcomes of Lymph Node Dissection for Non-metastatic Pancreatic Neuroendocrine Tumors: A Propensity Score-Weighted Analysis of the National Cancer Database
Annals of surgical oncology 2019 Sep;26(9):2722-2729
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31209670
BACKGROUND: Although the National Comprehensive Cancer Network (NCCN) guidelines recommend use of lymph node dissection (LND) in patients with pancreatic neuroendocrine tumors (pNETs) > 2 cm, there is limited evidence to support the association between use of LND and overall survival (OS). METHODS: Patients with resected pNETs were identified in the National Cancer Database (2004-2014). The inverse probability of treatment weighting (IPTW) method was used to reduce the selection bias. IPTW-adjusted Kaplan-Meier curves and Cox proportional hazards models were used to compare OS of patients in different treatment groups. RESULTS: A total of 2664 patients diagnosed met the study entry criteria. Of these, 2132 patients (80.6%) received LND, with a median of nine nodes removed. Positive nodes were identified in 28.0% of patients who underwent LND. IPTW-adjusted Kaplan-Meier analysis showed that median OS was similar between the LND and LND-omitted groups (152.8 vs. 147.3 months; p = 0.61). In IPTW-adjusted Cox proportional hazards regression analysis, LND was not associated with an OS benefit (hazard ratio [HR] 1.15, 95% confidence interval [CI] 0.94-1.42; p = 0.18). The results were consistent across subgroups stratified by clinical T and N stages. Among patients with lymph node metastasis, the number of removed nodes (NRN) above the median was not associated with an improved OS (HR 0.82, 95% CI 0.60-1.13; p = 0.22). CONCLUSIONS: LND had no additional therapeutic benefit among patients undergoing resection for pNETs. The present findings should be considered when managing patients with resectable pNETs.
doi: https://doi.org/10.1245/s10434-019-07506-5
- Dissecting the Stromal Signaling and Regulation of Myeloid Cells and Memory Effector T Cells in Pancreatic Cancer
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Sep;25(17):5351-5363
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31186314
PURPOSE: Myeloid cells are a prominent immunosuppressive component within the stroma of pancreatic ductal adenocarcinoma (PDAC). Previously, targeting myeloid cells has had limited success. Here, we sought to target the myeloid cells through modifying a specific stromal component. EXPERIMENTAL DESIGN: A murine model of metastatic PDAC treated with an irradiated whole-cell PDAC vaccine and PDAC specimens from patients treated with the same type of vaccine were used to assess the immune-modulating effect of stromal hyaluronan (HA) degradation by PEGPH20. RESULTS: Targeting stroma by degrading HA with PEGPH20 in combination with vaccine decreases CXCL12/CXCR4/CCR7 immunosuppressive signaling axis expression in cancer-associated fibroblasts, myeloid, and CD8+ T cells, respectively. This corresponds with increased CCR7- effector memory T-cell infiltration, an increase in tumor-specific IFNγ, and improved survival. In the stroma of human PDACs treated with the same vaccine, decreased stromal CXCR4 expression significantly correlated with decreased HA and increased cytotoxic activities, suggesting CXCR4 is an important therapeutic target. CONCLUSIONS: This study represents the first to dissect signaling cascades following PDAC stroma remodeling via HA depletion, suggesting this not only overcomes a physical barrier for immune cell trafficking, but alters myeloid function leading to downstream selective increases in effector memory T-cell infiltration and antitumor activity.
doi: https://doi.org/10.1158/1078-0432.CCR-18-4192
- Pancreatobiliary-type intraductal papillary mucinous neoplasm of the pancreas may have 2 subtypes with distinct clinicopathologic and genetic features
Human pathology 2019 Sep;91():26-35
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31175918
We recently experienced cases of pancreatobiliary-type intraductal papillary mucinous neoplasms (PB-IPMNs) with imaging features resembling pancreatic ductal adenocarcinomas (PDACs), and histologic appearance of purely pancreatobiliary morphology and highly distorted papillary growth, which led to the present study aiming to systematically investigate PB-IPMNs in comparison with PDACs. Surgical cases of PB-IPMNs (n = 31) and PDACs (n = 24) were examined. PB-IPMNs were classified into monotypic tumors (n = 12; 39%) consisting of entirely high-grade pancreatobiliary-type neoplastic cells and polytypic cases (n = 19; 61%) associated with components of low-grade dysplasia and/or other histologic types (eg, gastric, intestinal, or oncocytic types). Clinically, monotypic PB-IPMNs less commonly had dilatation of the ampullary orifice (0% versus 74%) and mucin hypersecretion (17% versus 89%) than did polytypic cases. In most cases of monotypic PB-IPMNs, cystic dilatation of the lesional ducts was less obvious on imaging; therefore, 33% were radiologically diagnosed as PDACs. Histologically, intraductal tumors in monotypic cases showed a highly complex papillary architecture with tubular/cribriform glands and irregular branching, and all these cases were associated with invasive malignancy. GNAS mutations were detected in polytypic PB-IPMNs (6/19; 32%), but there were no GNAS mutations in monotypic cases. The recurrence-free survival of patients with monotypic PB-IPMN or PDAC was similar and significantly worse than that of patients with polytypic PB-IPMN. In conclusion, some cases of monotypic PB-IPMNs lacked the classic characteristics of IPMNs and shared features with PDACs, raising the possibility that these cases may be better classified as a papillary variant of PDACs rather than IPMNs.
doi: https://doi.org/10.1016/j.humpath.2019.05.010
- Cross Validation of the Monoclonal Antibody Das-1 in Identification of High-Risk Mucinous Pancreatic Cystic Lesions
Gastroenterology 2019 09;157(3):720-730.e2
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31175863
BACKGROUND & AIMS: Although pancreatic cystic lesions (PCLs) are frequently and incidentally detected, it is a challenge to determine their risk of malignancy. In immunohistochemical and enzyme-linked immunosorbent assay (ELISA) analyses of tissue and cyst fluid from pancreatic intraductal papillary mucinous neoplasms, the monoclonal antibody Das-1 identifies those at risk for malignancy with high levels of specificity and sensitivity. We aimed to validate the ability of Das-1 to identify high-risk PCLs in comparison to clinical guidelines and clinical features, using samples from a multicenter cohort. METHODS: We obtained cyst fluid samples of 169 PCLs (90 intraductal papillary mucinous neoplasms, 43 mucinous cystic neoplasms, and 36 non-mucinous cysts) from patients undergoing surgery at 4 tertiary referral centers (January 2010 through June 2017). Histology findings from surgical samples, analyzed independently and centrally re-reviewed in a blinded manner, were used as the reference standard. High-risk PCLs were those with invasive carcinomas, high-grade dysplasia, or intestinal-type intraductal papillary mucinous neoplasms with intermediate-grade dysplasia. An ELISA with Das-1 was performed in parallel using banked cyst fluid samples. We evaluated the biomarker’s performance, generated area under the curve values, and conducted multivariate logistic regression using clinical and pathology features. RESULTS: The ELISA for Das-1 identified high-risk PCLs with 88% sensitivity, 99% specificity, and 95% accuracy, at a cutoff optical density value of 0.104. In 10-fold cross-validation analysis with 100 replications, Das-1 identified high-risk PCLs with 88% sensitivity and 98% specificity. The Sendai, Fukuoka, and American Gastroenterological Association guideline criteria identified high-risk PCLs with 46%, 52%, and 74% accuracy (P for comparison to Das-1 ELISA <.001). When we controlled for Das-1 in multivariate regression, main pancreatic duct dilation >5 mm (odds ratio, 14.98; 95% confidence interval, 2.63-108; P < .0012), main pancreatic duct dilation ≥1 cm (odds ratio, 47.9; 95% confidence interval, 6.39-490; P < .0001), and jaundice (odds ratio, 6.16; 95% confidence interval, 1.08-36.7; P = .0397) were significantly associated with high-risk PCLs. CONCLUSIONS: We validated the ability of an ELISA with the monoclonal antibody Das-1 to detect PCLs at risk for malignancy with high levels of sensitivity and specificity. This biomarker might be used in conjunction with clinical guidelines to identify patients at risk for malignancy.
doi: https://doi.org/10.1053/j.gastro.2019.05.014
- Effective Delivery of a Microtubule Polymerization Inhibitor Synergizes with Standard Regimens in Models of Pancreatic Ductal Adenocarcinoma
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Sep;25(18):5548-5560
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31175095
PURPOSE: Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer that is broadly chemoresistant, due in part to biophysical properties of tumor stroma, which serves as a barrier to drug delivery for most classical chemotherapeutic drugs. The goal of this work is to evaluate the preclinical efficacy and mechanisms of PTC596, a novel agent with potent anticancer properties in vitro and desirable pharmacologic properties in vivo.Experimental Design: We assessed the pharmacology, mechanism, and preclinical efficacy of PTC596 in combination with standards of care, using multiple preclinical models of PDA. RESULTS: We found that PTC596 has pharmacologic properties that overcome the barrier to drug delivery in PDA, including a long circulating half-life, lack of P-glycoprotein substrate activity, and high systemic tolerability. We also found that PTC596 combined synergistically with standard clinical regimens to improve efficacy in multiple model systems, including the chemoresistant genetically engineered “KPC” model of PDA. Through mechanistic studies, we learned that PTC596 functions as a direct microtubule polymerization inhibitor, yet a prior clinical trial found that it lacks peripheral neurotoxicity, in contrast to other such agents. Strikingly, we found that PTC596 synergized with the standard clinical backbone regimen gemcitabine/nab-paclitaxel, yielding potent, durable regressions in a PDX model. Moreover, similar efficacy was achieved in combination with nab-paclitaxel alone, highlighting a specific synergistic interaction between two different microtubule-targeted agents in the setting of pancreatic ductal adenocarcinoma. CONCLUSIONS: These data demonstrate clear rationale for the development of PTC596 in combination with standard-of-care chemotherapy for PDA.
doi: https://doi.org/10.1158/1078-0432.CCR-18-3281
- A Novel Oxoglutarate Dehydrogenase-Like Mediated miR-214/TWIST1 Negative Feedback Loop Inhibits Pancreatic Cancer Growth and Metastasis
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Sep;25(17):5407-5421
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31175094
PURPOSE: As a main rate-limiting subunit of the 2-oxoglutarate dehydrogenase multienzyme complex, oxoglutarate dehydrogenase like (OGDHL) is involved in the tricarboxylic acid cycle, and frequently downregulated in human carcinoma and suppresses tumor growth. However, little is known about the role of OGDHL in human cancer, especially pancreatic cancer. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by OGDHL modulating pancreatic cancer progression. EXPERIMENTAL DESIGN: The expression and functional analysis of OGDHL, miR-214, and TWIST1 in human pancreatic cancer tissues, cell lines, and xenograft tumor model were investigated. The correlations between OGDHL and those markers were analyzed. RESULTS: OGDHL was downregulated in human pancreatic cancer and predicted poor prognosis. OGDHL overexpression inhibited migration and invasion of pancreatic cancer cells and suppressed pancreatic cancer tumor growth. OGDHL was shown to be negatively regulated by miR-214. TWIST1 upregulation induced miR-214 expression in pancreatic cancer. OGDHL suppressed TWIST1 expression through promoting ubiquitin-mediated proteasomal degradation of HIF1α and regulating AKT pathways. A combination of OGDHL downregulation and TWIST1 and miR-214 overexpression predicted worse prognosis in patients with pancreatic cancer. CONCLUSIONS: We demonstrated the prognostic value of OGDHL, miR-214, and TWIST1 in pancreatic cancer, and elucidated a novel pathway in OGDHL-regulated inhibition of pancreatic cancer tumorigenesis and metastasis. These findings may lead to new targeted therapy for pancreatic cancer through regulating OGDHL, miR-214, and TWIST1.
doi: https://doi.org/10.1158/1078-0432.CCR-18-4113
- The Pathologic and Genetic Characteristics of the Intestinal Subtype of Intraductal Papillary Neoplasms of the Bile Duct
The American journal of surgical pathology 2019 Sep;43(9):1212-1220
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31166202
The present study aimed to identify the pathologic and genetic characteristics of intestinal subtype of intraductal papillary neoplasm of the bile duct (iIPNB) showing columnar cells with pseudostratified, cigar-shaped nuclei, and basophilic or amphophilic cytoplasm with the diffuse immunohistochemical expression of CK20 and/or CDX2. A total of 34 cases of iIPNB were pathologically examined according to their anatomic location (the bile duct) and were then compared with the intestinal subtype of intraductal papillary mucinous neoplasm (iIPMN) of the pancreas (n=22). Mutations of 26 somatic genes were examined in formalin-fixed paraffin-embedded tissue specimens from 21 cases of iIPNB using the TruSight Tumor 26 gene panel and next-generation sequencing. iIPNB cases were divided into intrahepatic (n=6) and extrahepatic (n=28) categories. Intrahepatic IPNBs showed a less-complicated villous-papillary pattern, while extrahepatic IPNBs showed a papillary pattern with tubular and/or villous components and predominant high-grade dysplasia with complicated architectures. MUC5AC was frequently and extensively expressed in intrahepatic iIPNBs and iIPMNs but not in extrahepatic iIPNBs. CD10 was frequently expressed in extrahepatic IPNBs but not in intrahepatic iIPNBs or iIPMN. Genetic mutations of TP53 and PIK3CA, which were infrequent or absent in iIPMNs, were frequently detected in extrahepatic iIPNBs, while KRAS and GNAS, which were commonly observed in iIPMNs, were frequently detected in intrahepatic iIPNBs. Intrahepatic iIPNBs showed villous-papillary growth with features reminiscent of iIPMNs, while extrahepatic iIPNBs showed papillary growth with tubular and/or villous components, complicated histology and variable differences from iIPMNs, suggesting differences in the tumorigenesis of iIPNBs along the biliary tree.
doi: https://doi.org/10.1097/PAS.0000000000001295
- Axon Guidance Molecules Promote Perineural Invasion and Metastasis of Orthotopic Pancreatic Tumors in Mice
Gastroenterology 2019 09;157(3):838-850.e6
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31163177
BACKGROUND & AIMS: Little is known about mechanisms of perineural invasion (PNI) by pancreatic ductal adenocarcinomas (PDAs) or other tumors. Annexin A2 (ANXA2) regulates secretion of SEMA3D, an axon guidance molecule, which binds and activates the receptor PLXND1 to promote PDA invasion and metastasis. We investigated whether axon guidance molecules promote PNI and metastasis by PDA cells in mice. METHODS: We performed studies in a dorsal root ganglion (DRG) invasion system, wild-type C57BL/6 mice (controls), mice with peripheral sensory neuron-specific disruption of PlxnD1 (PLAC mice), LSL-KRASG12D/+;LSL-TP53R172H/+;PDX-1-CRE+/+ (KPC) mice, and KPC mice crossed with ANXA2-knockout mice (KPCA mice). PDA cells were isolated from KPC mice and DRG cells were isolated from control mice. Levels of SEMA3D or ANXA2 were knocked down in PDA cells with small hairpin and interfering RNAs and cells were analyzed by immunoblots in migration assays, with DRGs and with or without antibodies against PLXND1. PDA cells were injected into the pancreas of control and PLAC mice, growth of tumors was assessed, and tumor samples were analyzed by histology. DRG cells were incubated with SEMA3D and analyzed by live imaging. We measured levels of SEMA3D and PLXND1 in PDA specimens from patients with PNI and calculated distances between tumor cells and nerves. RESULTS: DRG cells increase the migration of PDC cells in invasion assays; knockdown of SEMA3D in PDA cells or antibody blockade of PLXND1 on DRG cells reduced this invasive activity. In mice, orthotopic tumors grown from PDA cells with knockdown of SEMA3D, and in PLAC mice, orthotopic tumors grown from PDA cells, had reduced innervation and formed fewer metastases than orthotopic tumors grown from PDA cells in control mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI. CONCLUSIONS: DRG cells increase the migratory and invasive activities of pancreatic cancer cells, via secretion of SEMA3D by pancreatic cells and activation of PLXND1 on DRGs. Knockdown of SEMA3D and loss of neural PLXND1 reduces innervation of orthotopic PDAs and metastasis in mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI. Strategies to disrupt the axon guidance pathway mediated by SEMA3D and PLXND1 might be developed to slow progression of PDA.
doi: https://doi.org/10.1053/j.gastro.2019.05.065
- Results from a Phase IIb, Randomized, Multicenter Study of GVAX Pancreas and CRS-207 Compared with Chemotherapy in Adults with Previously Treated Metastatic Pancreatic Adenocarcinoma (ECLIPSE Study)
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Sep;25(18):5493-5502
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31126960
PURPOSE: Limited options exist for patients with advanced pancreatic cancer progressing after 1 or more lines of therapy. A phase II study in patients with previously treated metastatic pancreatic cancer showed that combining GVAX pancreas (granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated Listeria monocytogenes expressing mesothelin) resulted in median overall survival (OS) of 6.1 months, which compares favorably with historical OS achieved with chemotherapy. In the current study, we compared Cy/GVAX + CRS-207, CRS-207 alone, and standard chemotherapy in a three-arm, randomized, controlled phase IIb trial. PATIENTS AND METHODS: Patients with previously treated metastatic pancreatic adenocarcinoma were randomized 1:1:1 to receive Cy/GVAX + CRS-207 (arm A), CRS-207 (arm B), or physician’s choice of single-agent chemotherapy (arm C). The primary cohort included patients who had failed ≥2 prior lines of therapy, including gemcitabine. The primary objective compared OS between arms A and C in the primary cohort. The second-line cohort included patients who had received 1 prior line of therapy. Additional objectives included OS between all treatment arms, safety, and tumor responses. RESULTS: The study did not meet its primary efficacy endpoint. At the final study analysis, median OS [95% confidence interval (CI)] in the primary cohort (N = 213) was 3.7 (2.9-5.3), 5.4 (4.2-6.4), and 4.6 (4.2-5.7) months in arms A, B, and C, respectively, showing no significant difference between arm A and arm C [P = not significant (NS), HR = 1.17; 95% CI, 0.84-1.64]. The most frequently reported adverse events in all treatment groups were chills, pyrexia, fatigue, and nausea. No treatment-related deaths occurred. CONCLUSIONS: The combination of Cy/GVAX + CRS-207 did not improve survival over chemotherapy. (ClinicalTrials.gov ID: NCT02004262)See related commentary by Salas-Benito et al., p. 5435.
doi: https://doi.org/10.1158/1078-0432.CCR-18-2992
- Cholangiographic Tumor Classification for Simple Patient Selection Prior to Hepatopancreatoduodenectomy for Cholangiocarcinoma
Annals of surgical oncology 2019 Sep;26(9):2971-2979
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31102092
BACKGROUND: Hepatopancreatoduodenectomy (HPD) is employed for patients with laterally advanced cholangiocarcinoma. However, the survival benefit of this extended approach remains controversial. The aim of this study is to identify a tumor feature benefiting from HPD from the standpoint of long-term survival. PATIENTS AND METHODS: Patients with cholangiocarcinoma who underwent HPD with curative intent between 2001 and 2017 were retrospectively analyzed. Tumors were radiologically classified by preoperative cholangiogram. Diffuse type was defined as significant tumor/stricture located from the hilar to intrapancreatic duct; localized type was defined as tumor otherwise. Univariable and multivariable analyses were performed to identify prognostic indicators. RESULTS: Of 100 study patients, 28 (28%) patients had diffuse tumor type, while the remaining 72 (72%) patients had localized tumors. The former group showed significantly longer lateral length (43 versus 22 mm, P < 0.001) and more frequent pancreatic invasion (50% versus 32%, P = 0.110), advanced T classification (64% versus 49%, P = 0.185), and nodal metastasis (57% versus 47%, P = 0.504), compared with the latter group. The survival for patients with diffuse tumor type was significantly worse than that for patients with localized tumor type, with 5-year survival rates of 59.0% versus 26.3%, respectively (P = 0.003). Multivariable analysis identified four independent factors deteriorating long-term survival: cholangiographic diffuse tumor (P = 0.021), higher age (P = 0.020), percutaneous biliary drainage (P = 0.007), and portal vein resection (P = 0.007). CONCLUSIONS: Presurgical cholangiographic classification, diffuse or localized type, is a tumor-related factor closely associated with survival probability; therefore, it may be a useful feature for patient selection prior to HPD for cholangiocarcinoma.
doi: https://doi.org/10.1245/s10434-019-07457-x
- Understanding the mechanisms of reversal of type 2 diabetes
The lancet. Diabetes & endocrinology 2019 Sep;7(9):726-736
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31097391
Clinical and pathophysiological studies have shown type 2 diabetes to be a condition mainly caused by excess, yet reversible, fat accumulation in the liver and pancreas. Within the liver, excess fat worsens hepatic responsiveness to insulin, leading to increased glucose production. Within the pancreas, the β cell seems to enter a survival mode and fails to function because of the fat-induced metabolic stress. Removal of excess fat from these organs via substantial weight loss can normalise hepatic insulin responsiveness and, in the early years post-diagnosis, is associated with β-cell recovery of acute insulin secretion in many individuals, possibly by redifferentiation. Collectively, these changes can normalise blood glucose levels. Importantly, the primary care-based Diabetes Remission Clinical Trial (DiRECT) showed that 46% of people with type 2 diabetes could achieve remission at 12 months, and 36% at 24 months, mediated by weight loss. This major change in our understanding of the underlying mechanisms of disease permits a reassessment of advice for people with type 2 diabetes.
doi: https://doi.org/10.1016/S2213-8587(19)30076-2
- Rapid research autopsy is a stealthy but growing contributor to cancer research
Cancer 2019 Sep;125(17):2915-2919
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31090935
doi: https://doi.org/10.1002/cncr.32184
- Biomarkers to diagnose metastatic breast carcinoma to the pancreas: A case report and update
Diagnostic cytopathology 2019 Sep;47(9):912-917
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31087784
The patient is a 72-year-old female who presents with new onset jaundice. The patient has a past medical history significant for right-sided estrogen receptor (ER)-positive and left-sided ER-negative breast cancers in 2005 and 2009, respectively, and recent 1-year history of ER-positive right-sided breast cancer with bone and brain metastases. CT scan and endoscopic ultrasound (EUS) revealed a new 2 cm mass in the head of the pancreas, leading to EUS-guided fine-needle aspiration of the lesion. Pathologic workup revealed adenocarcinoma with signet-ring cells, representing either metastatic breast or primary pancreatic cancer. Immunohistochemistry and molecular diagnostic workup identified positive GATA-binding protein 3 (GATA3) immunoreactivity and a mutation in Erb-B2 receptor tyrosine kinase 2 (ERBB2), also known as human epidermal growth factor receptor 2 (HER2). Here, we review the diagnostic markers commonly used to differentiate metastatic breast vs primary pancreatic adenocarcinoma, and discuss the challenges of utilizing GATA3 immunoreactivity and ERBB2 mutations for diagnosis.
doi: https://doi.org/10.1002/dc.24210
- Pancreatic panniculitis in active systemic lupus erythematosus
Journal of cutaneous pathology 2019 Sep;46(9):688-690
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31081550
This report documents the case of a 64-year-old African-American female with new end-stage renal disease (ESRD), diagnosed with systemic lupus erythematosus (SLE) on renal biopsy and serologies including a positive ANA (>1:2560), positive anti-Sm antibodies, low titer anti-RNP antibodies, high titer anti-Ro antibodies, anti-dsDNA antibodies, lupus anticoagulant, and hypocomplementemia. She was also noted to have tender nodules on the bilateral shins. Excisional biopsy of one of the nodules showed marked fat necrosis with “ghost cells” and patchy basophilic granular debris consistent with pancreatic panniculitis. Further examination for pancreatic pathology showed an elevated lipase of 585 U/L (reference range 8-78 U/L) and amylase of 214 U/L (reference range 25-125 U/L). However, computed tomography imaging showed no evidence of pancreatitis or pancreatic tumors. This is very similar to another case recently reported in the literature. Similarities of these two cases (African-American females with lupus nephritis on dialysis) may represent a particular subset of SLE patients at increased risk for pancreatic panniculitis.
doi: https://doi.org/10.1111/cup.13493
- Regulation of pH by Carbonic Anhydrase 9 Mediates Survival of Pancreatic Cancer Cells With Activated KRAS in Response to Hypoxia
Gastroenterology 2019 09;157(3):823-837
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31078621
BACKGROUND & AIMS: Most pancreatic ductal adenocarcinomas (PDACs) express an activated form of KRAS, become hypoxic and dysplastic, and are refractory to chemo and radiation therapies. To survive in the hypoxic environment, PDAC cells upregulate enzymes and transporters involved in pH regulation, including the extracellular facing carbonic anhydrase 9 (CA9). We evaluated the effect of blocking CA9, in combination with administration of gemcitabine, in mouse models of pancreatic cancer. METHODS: We knocked down expression of KRAS in human (PK-8 and PK-1) PDAC cells with small hairpin RNAs. Human and mouse (KrasG12D/Pdx1-Cre/Tp53/RosaYFP) PDAC cells were incubated with inhibitors of MEK (trametinib) or extracellular signal-regulated kinase (ERK), and some cells were cultured under hypoxic conditions. We measured levels and stability of the hypoxia-inducible factor 1 subunit alpha (HIF1A), endothelial PAS domain 1 protein (EPAS1, also called HIF2A), CA9, solute carrier family 16 member 4 (SLC16A4, also called MCT4), and SLC2A1 (also called GLUT1) by immunoblot analyses. We analyzed intracellular pH (pHi) and extracellular metabolic flux. We knocked down expression of CA9 in PDAC cells, or inhibited CA9 with SLC-0111, incubated them with gemcitabine, and assessed pHi, metabolic flux, and cytotoxicity under normoxic and hypoxic conditions. Cells were also injected into either immune-compromised or immune-competent mice and growth of xenograft tumors was assessed. Tumor fragments derived from patients with PDAC were surgically ligated to the pancreas of mice and the growth of tumors was assessed. We performed tissue microarray analyses of 205 human PDAC samples to measure levels of CA9 and associated expression of genes that regulate hypoxia with outcomes of patients using the Cancer Genome Atlas database. RESULTS: Under hypoxic conditions, PDAC cells had increased levels of HIF1A and HIF2A, upregulated expression of CA9, and activated glycolysis. Knockdown of KRAS in PDAC cells, or incubation with trametinib, reduced the posttranscriptional stabilization of HIF1A and HIF2A, upregulation of CA9, pHi, and glycolysis in response to hypoxia. CA9 was expressed by 66% of PDAC samples analyzed; high expression of genes associated with metabolic adaptation to hypoxia, including CA9, correlated with significantly reduced survival times of patients. Knockdown or pharmacologic inhibition of CA9 in PDAC cells significantly reduced pHi in cells under hypoxic conditions, decreased gemcitabine-induced glycolysis, and increased their sensitivity to gemcitabine. PDAC cells with knockdown of CA9 formed smaller xenograft tumors in mice, and injection of gemcitabine inhibited tumor growth and significantly increased survival times of mice. In mice with xenograft tumors grown from human PDAC cells, oral administration of SLC-0111 and injection of gemcitabine increased intratumor acidosis and increased cell death. These tumors, and tumors grown from PDAC patient-derived tumor fragments, grew more slowly than xenograft tumors in mice given control agents, resulting in longer survival times. In KrasG12D/Pdx1-Cre/Tp53/RosaYFP genetically modified mice, oral administration of SLC-0111 and injection of gemcitabine reduced numbers of B cells in tumors. CONCLUSIONS: In response to hypoxia, PDAC cells that express activated KRAS increase expression of CA9, via stabilization of HIF1A and HIF2A, to regulate pH and glycolysis. Disruption of this pathway slows growth of PDAC xenograft tumors in mice and might be developed for treatment of pancreatic cancer.
doi: https://doi.org/10.1053/j.gastro.2019.05.004
- In Patients with Localized and Resectable Gastric Cancer, What is the Optimal Extent of Lymph Node Dissection-D1 Versus D2 Versus D3?
Annals of surgical oncology 2019 Sep;26(9):2912-2932
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31076930
BACKGROUND: Despite advances in the treatment of patients with gastric cancer, the debate over the optimal extent of lymphadenectomy continues. METHOD: A review of the classification, rationale for, and boundaries of lymphadenectomy is presented. A review of the available literature comparing D1 versus D2 versus D3 lymphadenectomy was performed and included randomized controlled trials, and prospective and retrospective comparative and non-comparative studies. RESULTS: Earlier studies demonstrated increased morbidity with D2 compared with D1 lymphadenectomy, with no significant survival benefit. More recent studies have demonstrated survival benefit of a pancreas and spleen-sparing D2 lymphadenectomy in patients with advanced, node-positive tumors. Para-aortic/D3 dissections contribute to increased morbidity, with no survival benefit. CONCLUSIONS: In patients with resectable gastric adenocarcinoma, a D2 lymph node dissection preserving the pancreas and spleen should be considered standard for optimal staging and treatment, provided it is performed by surgeons with sufficient expertise. Extended lymph node dissections beyond D2 should not be routinely performed as it has been shown to have increased morbidity, with no improvement in outcomes. While systemic chemotherapy should be considered standard in patients undergoing D2 lymphadenectomy, the role of adjuvant radiation continues to evolve.
doi: https://doi.org/10.1245/s10434-019-07417-5
- The role of rapid on-site evaluation on diagnostic accuracy of endoscopic ultrasound fine needle aspiration for pancreatic, submucosal upper gastrointestinal tract and adjacent lesions
Cytopathology : official journal of the British Society for Clinical Cytology 2019 Sep;30(5):499-503
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31034112
BACKGROUND AND AIM: Our aim was to assess adequacy and diagnostic accuracy of endoscopic ultrasound-fine needle aspiration (EUS-FNA) specimens with or without rapid on-site evaluation (ROSE) from pancreatic, upper gastrointestinal tract (UGIT) and adjacent masses. METHOD: A retrospective cohort study based on patients’ files who underwent EUS-FNA in Galilee Medical Center in a 4 years period. Number of needle passes, repeated EUS and ROSE effect on tissue adequacy and diagnostic accuracy were reported. RESULTS: One-hundred sixty-one patients were included. Ninety-three patients (57.7%) underwent EUS-FNA without ROSE (group A) compared to 68 patients (42.3%) with ROSE (group B). The most common location was in the pancreas (55% in group A vs 81% in group B). Addition of ROSE yielded a significantly higher specimen adequacy (65% in group A vs 92.6% in group B (Chi-Square < 0.0001, OR 6.72, 95% CI 2.45-18.38). The matching rate (accuracy) between ROSE diagnosis and final histopathological diagnosis was noticed in 61 out of 68 patients (89.7%, 95% CI 0.7993-0.9576). The Kappa coefficient correlations of matching rate between ROSE and final histopathological diagnosis of all lesion and in pancreatic lesions were 0.7558, (95% CI 0.625-0.887) and 0.7814, (95% CI 0.639-0.924), respectively. CONCLUSIONS: EUS-FNA with ROSE significantly improve specimen adequacy and was associated with high diagnostic accuracy.
doi: https://doi.org/10.1111/cyt.12712
- Acute Methamphetamine-Induced Hepatic and Pancreatic Ischemia
The American journal of forensic medicine and pathology 2019 Sep;40(3):285-288
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31033491
Methamphetamine is a central nervous system stimulant that induces arousal, a positive mood, cardiac stimulation, and an acute improvement in cognitive domains. Its illicit exploitation is rapidly growing in North America. Typically, extended use of the drug induces organ damage via vasoconstriction and subsequent ischemia. This case specifically discusses hepatic and pancreatic pathology resulting from methamphetamine overdose alongside an unusual discovery of globally necrotic von Meyenburg complexes.
doi: https://doi.org/10.1097/PAF.0000000000000486
- Pancreatic islet (of Langerhans) revisited
Histology and histopathology 2019 Sep;34(9):985-993
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31020988
One hundred and fifty years ago, Paul Langerhans described what would come to be known as pancreatic ‘islet of Langerhans’. Since then, we have accumulated knowledge about the pancreatic islet, the cells that exist there and the hormones secreted by these cells. The increasing prevalence of obesity, diabetes and Alzheimer’s disease in the population (three conditions that are linked to pancreatic islet function), the islet has been playing a significant role in endocrinological and metabolic studies searching how we can protect the pancreatic islet and its cell content, or how we can regenerate it. This review will be interested in the most recent and relevant aspects of knowledge regarding the pancreatic islet, always mentioning the evolution of knowledge and future perspectives for the treatment of diabetes and Alzheimer’s disease. The most recent research with microRNAs and islet culture and pseudoislet culture (organoids) allows predicting advances in knowledge with new drugs to act on the islet/cells (such as the hormone glucagon-like peptide (GLP) -1) as well as induction of other islet cells like alpha-cells and delta-cells to transform into beta-cells.
doi: https://doi.org/10.14670/HH-18-118
- Keratin 19-expressing hepatocellular carcinoma and small-duct type intrahepatic cholangiocarcinoma show a similar postoperative clinical course but have distinct genetic features
Histopathology 2019 Sep;75(3):385-393
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31017316
AIMS: The present study aimed to systematically compare clinicopathological and genetic features between keratin 19 (K19)-expressing hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). METHODS AND RESULTS: Consecutive cases of HCC (n = 430) were classified into K19+ and K19- using immunohistochemistry. ICCA cases were also separated into small-(S-iCCA; n = 36) and large-duct types (n = 22) based on recently proposed criteria, with the former being used in the present study. Mutational hot-spots in TERT, CTNNB1, KRAS and IDH1 were sequenced. Twenty-six cases (6%) of HCC expressed K19. K19+ HCC was more strongly associated with chronic hepatitis B than K19- HCC and S-iCCA (46% versus 17% and 6%; both P < 0.001). Lymph node metastasis was observed in K19+ HCC (8%) and S-iCCA (22%), but was exceptional in K19- HCC (1%). K19+ HCC had TERT promoter mutations less frequently than K19- HCC (31% versus 59%; P = 0.022), and lacked alterations in KRAS and IDH1. CTNNB1 mutations were similarly observed in K19+ and K19- HCC (23% and 19%, respectively), but rare in S-iCCA (3%). The postoperative survival curve of K19+ HCC was almost identical to that of S-iCCA in the first 5 years (approximately 50% at 5 years), and significantly worse than that of K19- HCC (P = 0.040). Extrahepatic recurrence was more common in K19+ HCC (50%) and S-iCCA (35%) than in K19- HCC (15%) (P = 0.001). CONCLUSIONS: Although K19+ HCC and S-iCCA showed similar biological behaviours, they did not share any driver gene mutations, suggesting the possible involvement of epigenetic alterations in the iCCA-like features of K19+ HCC.
doi: https://doi.org/10.1111/his.13884
- Addition of analysis of KRAS mutation or immunohistochemistry with MUC1 and carcinoembryonic antigen improves the diagnostic performance of fine needle aspiration cytology for the diagnosis of pancreatic carcinoma
Cytopathology : official journal of the British Society for Clinical Cytology 2019 Sep;30(5):485-491
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30929285
BACKGROUND: Pancreatic adenocarcinoma (PAC) is a health problem because of high lethality, increasing incidence and the absence of an early diagnosis. Biopsy by fine needle aspiration guided by endoscopic ultrasound has allowed obtaining tissue for cytopathological analysis, but there are several problems with their interpretation. We aimed to compare the diagnostic performance of the cytopathological analysis with the addition of either an immunohistochemical (IHC) panel or the KRAS mutation for the diagnosis of PAC. METHODS: We evaluated 62 pancreatic lesions by fine needle aspiration guided by endoscopic ultrasound, applying an IHC panel with mucin (MUC)-1, MUC4, carcinoembryonic antigen (CEA) and p53. All cases also had a KRAS mutation determination. Three cytopathologists blinded to clinical data and the KRAS status reviewed the cytology independently. We calculated diagnostic performances for the cytology alone, cytology+IHC and cytology+KRAS to show the best method to diagnose PAC. RESULTS: From 62 samples, 50 (80.6%) were PAC and 12 benign lesions. The cytopathological analysis correctly interpreted 26 malignant and 12 non-neoplastic cases (sensitivity 52%, specificity 100% and diagnostic accuracy 61.3%). The KRAS mutation was present in 88% of PAC. The cytology+ KRAS mutation increased the sensitivity by 10% and the diagnostic accuracy by 8%. The sensitivity increased by 2% adding either MUC1 or CEA to the cytology, and the diagnostic accuracy by 10 or 18%, respectively. CONCLUSION: The addition of IHC either with CEA or MUC1 improved the diagnostic performance of the cytology alone to diagnose PAC. The cytology + IHC evaluation was superior to the cytology + KRAS mutation to diagnose PAC.
doi: https://doi.org/10.1111/cyt.12697
- IL-33 overexpression in gallbladder cancers associated with pancreatobiliary maljunction
Histopathology 2019 Sep;75(3):365-375
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30882917
AIMS: To investigate whether genetic or inflammatory pro-oncogenic factors are relevant to the increased risk of gallbladder cancers in patients with pancreaticobiliary maljunction (PBM). METHODS AND RESULTS: Mutations in KRAS exon 2 were examined by a highly sensitive, droplet digital PCR platform using surgically resected specimens of PBM-associated (n = 31) and non-associated gallbladder cancers (n = 49). The tissue expression of IL-6 and IL-33, which are suspected to promote biliary carcinogenesis, was analysed by quantitative real-time PCR and in-situ hybridisation. The incidence of KRAS mutations was similarly low in PBM-associated (five of 32 cases; 16%) and non-associated cancers (four of 49 cases; 8%) (P = 0.272). The tissue expression of IL-33 mRNA, but not IL-6 mRNA, was significantly higher in PBM-associated gallbladder cancers than in gallbladder cancers without PBM (P = 0.004). A similar degree of IL-33 overexpression was also observed in the background non-cancerous mucosa in cases of PBM-associated gallbladder cancers, and was significantly greater than that in PBM cases with cholecystitis alone (P < 0.001). The results of in-situ hybridisation indicated that the source of IL-33 production in PBM-associated carcinomas was the endothelium, cancer cells and non-neoplastic biliary epithelium. In a combined PBM-associated and non-associated cohort, IL-33 overexpression in gallbladder cancers correlated with less aggressive features (e.g. a lower pT stage and longer overall survival), similar to recently reported findings on large-duct cholangiocarcinomas. CONCLUSIONS: KRAS mutations do not appear to be associated with a high risk of malignancy in PBM, while IL-33 overexpression may provide a pro-oncogenic microenvironment in the gallbladder mucosa of patients with PBM.
doi: https://doi.org/10.1111/his.13863
- Updated Alternative Fistula Risk Score (ua-FRS) to Include Minimally Invasive Pancreatoduodenectomy: Pan-European Validation
Annals of surgery 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30829699
OBJECTIVE: The aim of the study was to validate and optimize the alternative Fistula Risk Score (a-FRS) for patients undergoing minimally invasive pancreatoduodenectomy (MIPD) in a large pan-European cohort. BACKGROUND: MIPD may be associated with an increased risk of postoperative pancreatic fistula (POPF). The a-FRS could allow for risk-adjusted comparisons in research and improve preventive strategies for high-risk patients. The a-FRS, however, has not yet been validated specifically for laparoscopic, robot-assisted, and hybrid MIPD. METHODS: A validation study was performed in a pan-European cohort of 952 consecutive patients undergoing MIPD (543 laparoscopic, 258 robot-assisted, 151 hybrid) in 26 centers from 7 countries between 2007 and 2017. The primary outcome was POPF (International Study Group on Pancreatic Surgery grade B/C). Model performance was assessed using the area under the receiver operating curve (AUC; discrimination) and calibration plots. Validation included univariable screening for clinical variables that could improve performance. RESULTS: Overall, 202 of 952 patients (21%) developed POPF after MIPD. Before adjustment, the original a-FRS performed moderately (AUC 0.68) and calibration was inadequate with systematic underestimation of the POPF risk. Single-row pancreatojejunostomy (odds ratio 4.6, 95 confidence interval [CI] 2.8-7.6) and male sex (odds ratio 1.9, 95 CI 1.4-2.7) were identified as important risk factors for POPF in MIPD. The updated a-FRS, consisting of body mass index, pancreatic texture, duct size, and male sex, showed good discrimination (AUC 0.75, 95 CI 0.71-0.79) and adequate calibration. Performance was adequate for laparoscopic, robot-assisted, and hybrid MIPD and open pancreatoduodenectomy. CONCLUSIONS: The updated a-FRS (www.pancreascalculator.com) now includes male sex as a risk factor and is validated for both MIPD and open pancreatoduodenectomy. The increased risk of POPF in laparoscopic MIPD was associated with single-row pancreatojejunostomy, which should therefore be discouraged.
doi: https://doi.org/10.1097/SLA.0000000000003234
- Neuroendocrine Neoplasms Associated with Germline Pathogenic Variants in the Homologous Recombination Pathway
Endocrine pathology 2019 Sep;30(3):237-245
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30772928
Neuroendocrine neoplasms (NENs) have been primarily associated with germline pathogenic variants in genes involved in chromatin remodeling (MEN1), cell cycle control (CDKN1B), PI3K/mTOR signaling (TSC1/2, PTEN) as well as pseudohypoxia (VHL, SDHx). Recent work has implicated various genes involved in DNA repair pathways in the pathophysiology of a subset of pancreatic neuroendocrine neoplasms, including BRCA2, via the homologous recombination pathway (HRD). To date, germline variants in other HRD pathway genes have not been described to contribute to NEN. PALB2, RAD51C, and BARD1 are additional tumor suppressor genes which also mediate repair of double stranded DNA breaks through the HRD pathway and are implicated in hereditary breast (PALB2; BARD1) and ovarian (RAD51C) cancer. Here we report three cases of NEN associated with germline pathogenic variants in PALB2 (pancreatic NEN), RAD51C (thymic NEN), and BARD1 (pancreaticoduodenal NEN) respectively, further linking the DNA repair pathway to NENs.
doi: https://doi.org/10.1007/s12022-019-9569-4
- What Is the Peri-Pancreas Cystic Lesion?
Gastroenterology 2019 09;157(3):622-623
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30615877
doi: https://doi.org/10.1053/j.gastro.2018.12.029
- Acute Pancreatitis Caused by Isolated Pancreatic Metastasis From Uterine Choriocarcinoma
International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 2019 Sep;38(5):430-434
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30028356
Choriocarcinoma is an aggressive gestational trophoblastic neoplasia known for its widely metastatic potential. However, isolated pancreatic metastasis is an extremely rare occurrence and has not been documented in the English literature to the best of our knowledge. The metastatic deposits in the index case led to widespread hemorrhage and necrosis of the pancreatic parenchyma, causing severe acute pancreatitis. The patient succumbed to her illness before chemotherapy was administered. Thus, we present an autopsy case of a uterine choriocarcinoma with isolated pancreatic metastasis presenting as severe acute pancreatitis in a 27-yr-old woman following a molar pregnancy.
doi: https://doi.org/10.1097/PGP.0000000000000532
- Medium and long-term risks of specific cardiovascular diseases in survivors of 20 adult cancers: a population-based cohort study using multiple linked UK electronic health records databases
Lancet (London, England) 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31443926
BACKGROUND: The past few decades have seen substantial improvements in cancer survival, but concerns exist about long-term cardiovascular disease risk in survivors. Evidence is scarce on the risks of specific cardiovascular diseases in survivors of a wide range of cancers to inform prevention and management. In this study, we used large-scale electronic health records data from multiple linked UK databases to address these evidence gaps. METHODS: For this population-based cohort study, we used linked primary care, hospital, and cancer registry data from the UK Clinical Practice Research Datalink to identify cohorts of survivors of the 20 most common cancers who were 18 years or older and alive 12 months after diagnosis and controls without history of cancer, matched for age, sex, and general practice. We compared risks for a range of cardiovascular disease outcomes using crude and adjusted Cox models. We fitted interactions to investigate effect modification, and flexible parametric survival models to estimate absolute excess risks over time. FINDINGS: Between Jan 1, 1990, and Dec 31, 2015, 126 120 individuals with a diagnosis of a cancer of interest still being followed up at least 1 year later were identified and matched to 630 144 controls. After exclusions, 108 215 cancer survivors and 523 541 controls were included in the main analyses. Venous thromboembolism risk was elevated in survivors of 18 of 20 site-specific cancers compared with that of controls; adjusted hazard ratios (HRs) ranged from 1·72 (95% CI 1·57-1·89) in patients after prostate cancer to 9·72 (5·50-17·18) after pancreatic cancer. HRs decreased over time, but remained elevated more than 5 years after diagnosis. We observed increased risks of heart failure or cardiomyopathy in patients after ten of 20 cancers, including haematological (adjusted HR 1·94, 1·66-2·25, with non-Hodgkin lymphoma; 1·77, 1·50-2·09, with leukaemia; and 3·29, 2·59-4·18, with multiple myeloma), oesophageal (1·96, 1·46-2·64), lung (1·82, 1·52-2·17) kidney (1·73, 1·38-2·17) and ovarian (1·59, 1·19-2·12). Elevated risks of arrhythmia, pericarditis, coronary artery disease, stroke, and valvular heart disease were also observed for multiple cancers, including haematological malignancies. HRs for heart failure or cardiomyopathy and venous thromboembolism were greater in patients without previous cardiovascular disease and in younger patients. However, absolute excess risks were generally greater with increasing age. Increased risks of these outcomes seemed most pronounced in patients who had received chemotherapy. INTERPRETATION: Survivors of most site-specific cancers had increased medium-term to long-term risk for one or more cardiovascular diseases compared with that for the general population, with substantial variations between cancer sites. FUNDING: Wellcome Trust and Royal Society.
doi: https://doi.org/10.1016/S0140-6736(19)31674-5
- The Histone Demethylase KDM3A, Increased in Human Pancreatic Tumors, Regulates Expression of DCLK1 in and Promotes Tumorigenesis in Mice
Gastroenterology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31442435
BACKGROUND & AIMS: The histone lysine demethylase 3A (KDM3A) demethylates demethylates H3K9me1 and H3K9Me2 to increase gene transcription and is upregulated in tumors, including pancreatic tumors. We investigated its activities in pancreatic cancer cell lines and its regulation of the gene encoding doublecortin calmodulin-like kinase 1 (DCLK1), a marker of cancer stem cells. METHODS: We knocked down KDM3A in MiaPaCa-2 and S2-007 pancreatic cancer cell lines and overexpressed KDM3A in HPNE cells (a human pancreatic cell line); we evaluated cell migration, invasion, and spheroid formation under hypoxic and normoxic conditions. Nude mice were given orthotopic injections of S2-007 cells, with or without (control) knockdown of KDM3A, and HPNE cells, with or without (control) overexpression of KDM3A; tumor growth was assessed. We analyzed pancreatic tumor tissues from mice and pancreatic cancer cell lines by immunohistochemistry and immunoblotting. We performed RNA-seq analysis of MiaPaCa-2 and S2-007 cells with knockdown of KDM3A and evaluated localization of DCLK1 and KDM3A by immunofluorescence. We analyzed the cancer genome atlas for levels of KDM3A and DCLK1 mRNA in human pancreatic ductal adenocarcinoma (PDAC) tissues and association with patient survival time. RESULTS: Levels of KDM3A were increased in human pancreatic tumor tissues and cell lines, compared with adjacent non-tumor pancreatic tissues such as islet and acinar cells. Knockdown of KDM3A in S2-007 cells significantly reduced colony formation, invasion, migration, and spheroid formation, compared with control cells, and slowed growth of orthotopic tumors in mice. We identified KDM3A-binding sites in the DCLK1 promoter; S2-007 cells with knockdown of KDM3A had reduced levels of DCLK1. HPNE cells that overexpressed KDM3A formed foci and spheres in culture and formed tumors and metastases in mice, whereas control HPNE cells did not. Hypoxia induced sphere formation and increased levels of KDM3A in S2-007 cells and in HPNE cells that overexpressed DCLK1, but not control HPNE cells. Levels of KDM3A and DCLK1 mRNA were higher in human PDAC than non-tumor pancreatic tissues and correlated with shorter survival times of patients. CONCLUSIONS: We found human PDAC samples and pancreatic cancer cell lines to overexpress KDM3A. KDM3A increases expression of DCLK1, and levels of both proteins are increased in human PDAC samples. Knockdown of KDM3A in in pancreatic cancer cell lines reduced their invasive and sphere-forming activities in culture and formation of orthotopic tumors in mice. Hypoxia increased expression of KDM3A in pancreatic cancer cells. Strategies to disrupt this pathway might be developed for treatment of pancreatic cancer.
doi: https://doi.org/10.1053/j.gastro.2019.08.018
- Ovarian Steroid Cell Tumor in an Adolescent With Von Hippel-Lindau Syndrome: A Case Report and Review of the Literature
International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31433374
Von Hippel-Lindau (VHL) syndrome is an autosomal dominant genetic disorder caused by germline mutation of the VHL gene. It is associated with multiple neoplasias including hemangioblastoma, clear cell renal cell carcinoma, pheochromocytoma, and neuroendocrine tumors. Ovarian tumors are extremely rare in this syndrome. We describe the case of a 16-yr-old girl with a previous diagnosis of bilateral pheochromocytoma and several pancreatic neuroendocrine tumors in VHL syndrome context. Follow-up abdominal-pelvic magnetic resonance imaging revealed a 33 mm, well-circumscribed nodule in the right ovary. The patient was submitted to laparoscopic right salpingo-oophorectomy. Microscopically, the tumor consisted of polygonal cells with abundant microvacuolized clear cytoplasm arranged in a solid pattern. The neoplastic cells were immunohistochemically positive for inhibin and calretinin. A diagnosis of ovarian steroid cell tumor was made. Only 4 cases with this association have been reported to date. Of the previously described cases, only one concerns a child; the others were all adult women. All of them had a previous diagnosis of VHL syndrome and presented with secondary amenorrhea and/or hirsutism due to testosterone-secreting ovarian steroid cell tumors. Although extremely rare, the association between VHL syndrome and ovarian steroid cell tumor has been reported, and our case suggests there is a link between the 2 entities.
doi: https://doi.org/10.1097/PGP.0000000000000628
- ASO Author Reflections: Resection for Metastasis to the Pancreas-Worthwhile for Selected Patients
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31429018
doi: https://doi.org/10.1245/s10434-019-07621-3
- Treatment of disrupted and disconnected pancreatic duct in necrotizing pancreatitis: A systematic review and meta-analysis
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31473083
BACKGROUND: Necrotizing pancreatitis may lead to loss of integrity of the pancreatic duct, resulting in leakage of pancreatic fluid. Pancreatic duct disruption or disconnection is associated with a prolonged disease course and particular complications. Since a standard treatment for this condition is currently lacking, we performed a systematic review of the literature to compare outcomes of various treatment strategies. METHODS: A systematic review was performed according to the PRISMA guidelines in the PubMed, EMBASE and Cochrane databases. Included were articles considering the treatment of patients with disrupted or disconnected pancreatic duct resulting from acute necrotizing pancreatitis. RESULTS: Overall, 21 observational cohort studies were included comprising a total of 583 relevant patients. The most frequently used treatment strategies included endoscopic transpapillary drainage, endoscopic transluminal drainage, surgical drainage or resection, or combined procedures. Pooled analysis showed success rates of 81% (95%-CI: 60-92%) for transpapillary and 92% (95%-CI: 77-98%) for transluminal drainage, 80% (95%-CI: 67-89%) for distal pancreatectomy and 84% (95%-CI: 73-91%) for cyst-jejunostomy. Success rates did not differ between surgical procedures (cyst-jejunostomy and distal pancreatectomy (risk ratio = 1.06, p = .26)) but distal pancreatectomy was associated with a higher incidence of endocrine pancreatic insufficiency (risk ratio = 3.06, p = .01). The success rate of conservative treatment is unknown. DISCUSSION: Different treatment strategies for pancreatic duct disruption and duct disconnection after necrotizing pancreatitis show high success rates but various sources of bias in the available studies are likely. High-quality prospective, studies, including unselected patients, are needed to establish the most effective treatment in specific subgroups of patients, including timing of treatment and long-term follow-up.
doi: https://doi.org/10.1016/j.pan.2019.08.006
- Obesity and pancreatic cancer: An update of epidemiological evidence and molecular mechanisms
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31447281
Despite advances in therapy and achievements in translational research, pancreatic cancer (PC) remains an invariably fatal malignancy. Risk factors that affect the incidence of PC include diabetes, smoking, obesity, chronic pancreatitis, and diet. The growing worldwide obesity epidemic is associated with an increased risk of the most common cancers, including PC. Chronic inflammation, hormonal effects, circulating adipokines, and adipocyte-mediated inflammatory and immunosuppressive microenvironment are involved in the association of obesity with PC. Herein, we systematically review the epidemiology of PC and the biological mechanisms that may account for this association. Included in this review is a discussion of adipokine-mediated inflammation, lipid metabolism, and the interactions of adipocytes with cancer cells. We consider the influence of bariatric surgery on the risk of PC risk as well as potential molecular targets of therapy. Our review leads us to conclude that targeting adipose tissue to achieve weight loss may represent a new therapeutic strategy for preventing and treating PC.
doi: https://doi.org/10.1016/j.pan.2019.08.008
- A rational approach to postoperative surveillance for resected non-functional pancreatic neuro-endocrine tumours
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31445889
BACKGROUND: Non-functional pancreatic neuroendocrine tumours (NF-PNETs) are rare and have highly variable outcomes. Current guidelines recommend surveillance for NF-PNETs <2 cm. Patients who ultimately have surgical resection are at risk of disease recurrence, and data to support postoperative surveillance protocols are lacking. The aims of this study were to i) identify post-operative predictors of recurrence and ii) risk stratify patients at risk of recurrence. METHODS: Consecutive patients who underwent surgery for NF-PNETs between 2002 and 2015 were identified retrospectively. Data were collected on demographics, pre-operative laboratory results and histopathological tumour characteristics. Statistical analyses were based on penalised Cox-regression modelling and a decision-tree model. Comparison of the variables identified was performed using ROC curves to identify the most sensitive and specific variable associated with disease recurrence. RESULTS: We identified 73 patients (38 males) with a median age of 61.5 years (range: 31-79). The median period of follow-up was 49 months (5-131). During follow up, 10 deaths (13.9%) were recorded and disease recurrence occurred in 12 patients (16.4%). The Kaplan-Meier predicted 1-,3- and 5-year recurrence-free survival rates were 98.6% (95% CI = 95.9, 100%), 85.4% (76.9-94.8%) and 72% (58.7-88.2%) respectively. Cox multivariate analysis identified poor tumour differentiation (WHO G3 grade) and lymph node ratio (LNR) as independent predictors for recurrence (p < 0.05). A simple criterion of ‘tumour grade G3 or LNR ≥0.1’ was found to be sensitive and specific in detecting disease recurrence. CONCLUSION: Our results have identified a simple and sensitive criterion for risk stratifying post-resection surveillance. Prospective validation in larger patient cohort is now warranted.
doi: https://doi.org/10.1016/j.pan.2019.08.005
- A new role for the spleen: aggravation of the systemic inflammatory response in rats with severe acute pancreatitis
The American journal of pathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31430464
Little is known about the role of the spleen in mediating systemic inflammatory responses in severe acute pancreatitis (SAP). Here, we investigated the role played by the spleen in rats after SAP induction. Splenectomy was performed at designated time points after SAP induction. Pancreatic tissue and serum samples were collected and subjected to histological, immunohistochemical, and immunological analyses. Following SAP induction, the splenic immune response was enhanced during SAP progression, as shown by the increased diameter of the splenic periarterial lymphatic sheath and the thickness of the splenic marginal zone. Rats with splenectomy developed acute pancreatitis more slowly than rats without splenectomy. Additionally, pancreatic tissues of rats with splenectomy contained lower levels of serum amylase, tumor necrosis factor-α, and interleukin-6 and exhibited less acinar cell death, leucocyte infiltration, and interstitial oedema than those of rats without splenectomy. Compared with splenectomy alone, cotreatment with splenectomy and the administration of splenic cells originating from a rat with SAP 12 h after induction increased systemic inflammation in SAP rats. Splenic factors exacerbated SAP-associated liver and lung injury and accentuated intestinal mucosal barrier dysfunction. Splenectomy altered the serum cytokine profile in rats with SAP. In a rat model of SAP, the spleen exacerbated the systematic inflammatory responses and injury to multiple organs, indicating a new role for the spleen in SAP.
doi: https://doi.org/10.1016/j.ajpath.2019.07.008
- Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials
The lancet. Diabetes & endocrinology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31422062
BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists differ in their structure and duration of action and have been studied in trials of varying sizes and with different patient populations, with inconsistent effects on cardiovascular outcomes reported. We aimed to synthesise the available evidence by doing a systematic review and meta-analysis of cardiovascular outcome trials of these drugs. METHODS: We searched MEDLINE (via PubMed) and the Cochrane Central Register of Controlled Trials for eligible placebo-controlled trials reporting major adverse cardiovascular events (MACE; ie, cardiovascular death, stroke, or myocardial infarction) up to June 15, 2019. We did a meta-analysis using a random-effects model to estimate overall hazard ratios (HRs) for MACE, its components, death from any cause, hospital admission for heart failure, kidney outcomes, and key safety outcomes (severe hypoglycaemia, pancreatitis, and pancreatic cancer). We also examined MACE in several subgroups based on patient characteristics (history of cardiovascular disease, BMI, age, baseline HbA1c, and baseline estimated glomerular filtration rate), trial duration, treatment dosing interval, and structural homology. FINDINGS: Of 27 publications screened, seven trials, with a combined total of 56 004 participants, were included: ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), EXSCEL (exenatide), Harmony Outcomes (albiglutide), REWIND (dulaglutide), and PIONEER 6 (oral semaglutide). Overall, GLP-1 receptor agonist treatment reduced MACE by 12% (HR 0·88, 95% CI 0·82-0·94; p<0·0001). There was no statistically significant heterogeneity across the subgroups examined. HRs were 0·88 (95% CI 0·81-0·96; p=0·003) for death from cardiovascular causes, 0·84 (0·76-0·93; p<0·0001) for fatal or non-fatal stroke, and 0·91 (0·84-1·00; p=0·043) for fatal or non-fatal myocardial infarction. GLP-1 receptor agonist treatment reduced all-cause mortality by 12% (0·88, 0·83-0·95; p=0·001), hospital admission for heart failure by 9% (0·91, 0·83-0·99; p=0·028), and a broad composite kidney outcome (development of new-onset macroalbuminuria, decline in estimated glomerular filtration rate [or increase in creatinine], progression to end-stage kidney disease, or death attributable to kidney causes) by 17% (0·83, 0·78-0·89; p<0·0001), mainly due to a reduction in urinary albumin excretion. There was no increase in risk of severe hypoglycaemia, pancreatitis, or pancreatic cancer. INTERPRETATION: Treatment with GLP-1 receptor agonists has beneficial effects on cardiovascular, mortality, and kidney outcomes in patients with type 2 diabetes. FUNDING: None.
doi: https://doi.org/10.1016/S2213-8587(19)30249-9
- First-in-human Study of Mivebresib (ABBV-075), an Oral Pan-inhibitor of Bromodomain and Extra Terminal Proteins, in Patients with Relapsed/Refractory Solid Tumors
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31420359
PURPOSE: Bromodomain and extra-terminal (BET) proteins play important roles in transcriptional regulation relevant to cancer pathogenesis, and therapeutic targeting/inhibition of BET causes apoptosis of cancer cells in vitro In this first-in-human study of the pan-BET inhibitor mivebresib (ABBV-075) the safety profile, maximal tolerated dose (MTD), and recommended phase 2 dose (RP2D) were determined in patients with advanced solid tumors. EXPERIMENTAL DESIGN: A 3+3 dose escalation for different mivebresib dosing schedules (daily, Monday/Wednesday/Friday [M-W-F], 4 days on/3 off [4/7]) was followed by dose expansion in prostate cancer patients. Endpoints were safety, tolerability, pharmacokinetics, and preliminary antitumor activity. RESULTS: Seventy-two patients with solid tumors [14% uveal melanoma; 11% colorectal, 11% breast; 8% pancreatic; 7% head/neck; 49% others] were treated with mivebresib during dose escalation, and 12 additional patients with prostate cancer in expansion cohort. Most common TEAEs related to mivebresib were dysgeusia (49%), thrombocytopenia (48%), fatigue (26%) and nausea (25%). Most common grade 3/4 TEAEs related to mivebresib were thrombocytopenia (35%) and anemia (6%). Dose-limiting toxicities included thrombocytopenia (2mg daily; 4.5mg M-W-F), gastrointestinal bleed (2mg daily), hypertension (2-3mg 4/7), fatigue, decreased appetite, and aspartate aminotransferase elevation (4mg M-W-F). Of 61 evaluable patients from dose-escalation, 26 (43%) had stable disease and 35 (57%) had progressive disease. Median progression-free survival was 1.8 months (95%CI: 1.8,1.9). CONCLUSIONS: Based on safety and tolerability, mivebresib RP2D is 1.5mg for the daily schedule, 2.5mg for 4/7 and 3mg for M-W-F. Mivebresib has a tolerable safety profile and stable disease was observed in some patients with malignant solid tumors.
doi: https://doi.org/10.1158/1078-0432.CCR-19-0578
- Pancreatic tumor in type 1 autoimmune pancreatitis: a diagnostic challenge
BMC cancer 2019 Aug;19(1):814
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31419961
BACKGROUND: The co-occurrence of type 1 autoimmune pancreatitis (AIP) and pancreatic tumor (PaT) has been previously reported. Pure AIP cases have favorable prognosis and are primarily treated with steroids, while AIP cases with PaT are associated with poor prognosis where the primary management is pancreatic resection. However, it’s a challenge to timely identify the concurrent PaT in AIP because of their similar clinical and radiological manifestations. METHODS: We retrospectively reviewed the data in two medical centers from January 2010 to April 2019. The inclusion criteria were as follows: 1) completion of abdominal CT imaging before invasive procedures to the pancreas, 2) a final diagnosis of type 1 AIP using the 2011 international consensus diagnostic criteria, 3) follow-up duration of at least one month unless AIP and PaT were identified simultaneously. The presence of PaT in AIP was made based on histopathological confirmation, and the absence of PaT in AIP was defined as no pathological or radiological evidence of concurrent PaT. Clinical and radiological characteristics including gender, age, surveillance period, serum IgG4 and Ca-199 levels, biopsy, extrapancreatic involvement, CT and MR (if performed) imaging characteristics were compared between AIP with and without PaT. The Fisher’s exact test was used for qualitative variables, and nonparametric Mann-Whitney test for quantitative variables. A p value ≤0.05 was considered statistically significant. RESULTS: A total of 74 patients with type 1 AIP were included, of which 5 (6.7%) had the concurrent PaT. The subtypes were pancreatic ductal adenocarcinoma (3/5), solitary extramedullary plasmacytoma in the pancreas (1/5) and cholangiocarcinoma in the pancreatic segment (1/5), respectively. Gender (p = 0.044), the pattern of pancreatic enlargement (p = 0.003), heterogeneity (p = 0.015), low-density (p = 0.004) on CT and rim enhancement on MRI (p = 0.050) differed significantly between AIP with and without PaT. None of the low-density characteristics on CT or other assessed MRI characteristics could significantly differentiate the two groups (p>0.05). CONCLUSIONS: Female, focal pancreatic enlargement, pancreatic heterogeneity, low-density on CT and rim enhancement on MRI are suggestive of the concurrent PaT in type 1 AIP. The characteristics of low-density on CT or other MRI characteristics did not provide further diagnostic values.
doi: https://doi.org/10.1186/s12885-019-6027-0
- Perioperative Gemcitabine + Erlotinib Plus Pancreaticoduodenectomy for Resectable Pancreatic Adenocarcinoma: ACOSOG Z5041 (Alliance) Phase II Trial
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31418130
BACKGROUND: There is considerable interest in a neoadjuvant approach for resectable pancreatic ductal adenocarcinoma (PDAC). This study evaluated perioperative gemcitabine + erlotinib (G+E) for resectable PDAC. METHODS: A multicenter, cooperative group, single-arm, phase II trial was conducted between April 2009 and November 2013 (ACOSOG Z5041). Patients with biopsy-confirmed PDAC in the pancreatic head without evidence of involvement of major mesenteric vessels (resectable) were eligible. Patients (n = 123) received an 8-week cycle of G+E before and after surgery. The primary endpoint was 2-year overall survival (OS), and secondary endpoints included toxicity, response, resection rate, and time to progression. Resectability was assessed retrospectively by central review. The study closed early due to slow accrual, and no formal hypothesis testing was performed. RESULTS: Overall, 114 patients were eligible, consented, and initiated protocol treatment. By central radiologic review, 97 (85%) of the 114 patients met the protocol-defined resectability criteria. Grade 3+ toxicity was reported in 60% and 79% of patients during the neoadjuvant phase and overall, respectively. Twenty-two of 114 (19%) patients did not proceed to surgery; 83 patients (73%) were successfully resected. R0 and R1 margins were obtained in 67 (81%) and 16 (19%) resected patients, respectively, and 54 patients completed postoperative G+E (65%). The 2-year OS rate for the entire cohort (n = 114) was 40% (95% confidence interval [CI] 31-50), with a median OS of 21.3 months (95% CI 17.2-25.9). The 2-year OS rate for resected patients (n = 83) was 52% (95% CI 41-63), with a median OS of 25.4 months (95% CI 21.8-29.6). CONCLUSIONS: For resectable PDAC, perioperative G+E is feasible. Further evaluation of neoadjuvant strategies in resectable PDAC is warranted with more active systemic regimens.
doi: https://doi.org/10.1245/s10434-019-07685-1
- A multicenter, open-label, single-arm study of anamorelin (ONO-7643) in advanced gastrointestinal cancer patients with cancer cachexia
Cancer 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31415709
BACKGROUND: Cancer cachexia is characterized by weight loss and is associated with increased morbidity and mortality in patients with cancer. Anamorelin (ONO-7643; ANAM) is a novel and selective ghrelin receptor agonist that improves appetite, lean body mass (LBM), body weight, and anorexia. METHODS: This multicenter, open-label, single-arm study investigated the efficacy and safety of 100 mg anamorelin in 50 Japanese patients with advanced and unresectable gastrointestinal (colorectal, gastric, or pancreatic) cancer. ANAM was administered once daily over 12 weeks. The primary endpoint was the proportion of patients that maintained or gained LBM over the course of the study. Secondary endpoints included changes in LBM, body weight, quality of life (QoL), and nutritional status biomarkers. RESULTS: The proportion of patients who responded to treatment was 63.3% (95% CI, 48.3%-76.6%), with a least square mean ± SE change in LBM and body weight from baseline of 1.89 ± 0.36 kg and 1.41 ± 0.61 kg, respectively. Appetite-related questions on the QoL questionnaire showed that ANAM improved appetite. Adverse events occurred in 79.6% of patients, and the most common treatment-related adverse events were increased γ-glutamyl transpeptidase (8.2%), diabetes mellitus (6.1%), hyperglycemia (6.1%), and prolonged QRS complex (6.1%). CONCLUSIONS: ANAM improved anorexia and patients’ nutritional status, resulting in rapid increases in LBM and body weight in patients with advanced gastrointestinal cancer who had cancer cachexia. ANAM treatment was well tolerated over 12 weeks. ANAM is a potential clinically beneficial pharmacotherapeutic option for patients with advanced gastrointestinal cancer who have cancer cachexia.
doi: https://doi.org/10.1002/cncr.32406
- African American women with gum disease and tooth loss face higher pancreatic cancer risk
Cancer 2019 Aug;125(16):2719
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31355935
doi: https://doi.org/10.1002/cncr.32413
- Circulating Tumor DNA as a Clinical Test in Resected Pancreatic Cancer
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Aug;25(16):4973-4984
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31142500
PURPOSE: In research settings, circulating tumor DNA (ctDNA) shows promise as a tumor-specific biomarker for pancreatic ductal adenocarcinoma (PDAC). This study aims to perform analytical and clinical validation of a KRAS ctDNA assay in a Clinical Laboratory Improvement Amendments (CLIA) and College of American Pathology-certified clinical laboratory. EXPERIMENTAL DESIGN: Digital-droplet PCR was used to detect the major PDAC-associated somatic KRAS mutations (G12D, G12V, G12R, and Q61H) in liquid biopsies. For clinical validation, 290 preoperative and longitudinal postoperative plasma samples were collected from 59 patients with PDAC. The utility of ctDNA status to predict PDAC recurrence during follow-up was assessed. RESULTS: ctDNA was detected preoperatively in 29 (49%) patients and was an independent predictor of decreased recurrence-free survival (RFS) and overall survival (OS). Patients who had neoadjuvant chemotherapy were less likely to have preoperative ctDNA than were chemo-naïve patients (21% vs. 69%; P < 0.001). ctDNA levels dropped significantly after tumor resection. Persistence of ctDNA in the immediate postoperative period was associated with a high rate of recurrence and poor median RFS (5 months). ctDNA detected during follow-up predicted clinical recurrence [sensitivity 90% (95% confidence interval (CI), 74%-98%), specificity 88% (95% CI, 62%-98%)] with a median lead time of 84 days (interquartile range, 25-146). Detection of ctDNA during postpancreatectomy follow-up was associated with a median OS of 17 months, while median OS was not yet reached at 30 months for patients without ctDNA (P = 0.011). CONCLUSIONS: Measurement of KRAS ctDNA in a CLIA laboratory setting can be used to predict recurrence and survival in patients with PDAC.
doi: https://doi.org/10.1158/1078-0432.CCR-19-0197
- Arginine Starvation and Docetaxel Induce c-Myc-Driven hENT1 Surface Expression to Overcome Gemcitabine Resistance in ASS1-Negative Tumors
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Aug;25(16):5122-5134
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31113844
PURPOSE: The response to acute and long-term arginine starvation results in a conditional adaptive metabolic reprogramming that can be harnessed for therapeutic opportunities in ASS1-negative tumors. Here, we investigate the underlying biology of priming ASS1- tumors with arginine deiminase (ADI-PEG20) before treatment with gemcitabine (GEM) and docetaxel (DTX) in sarcoma, pancreatic cancer, and melanoma cell lines. EXPERIMENTAL DESIGN: ASS1- tumor cell lines were treated to create LTAT (long-term ADI treated) cell lines (ASS1+) and used for drug combination studies. Protein expression of ASS1, dCK, RRM2, E2F1, c-MYC, and hENT1 was measured. c-MYC activity was determined, live-cell immunofluorescent studies for hENT1, uptake assays of FITC-cytosine probe, and rescue studies with a c-MYC inhibitor were all determined in the presence or absence of the ADI-PEG20:GEM:DTX. RESULTS: In examining modulations within the pyrimidine pathway, we identified that the addition of DTX to cells treated with ADI-PEG20 resulted in translocation of stabilized c-Myc to the nucleus. This resulted in an increase of hENT1 cell-surface expression and rendered the cells susceptible to GEM. In vivo studies demonstrate that the combination of ADI-PEG20:GEM:DTX was optimal for tumor growth inhibition, providing the preclinical mechanism and justification for the ongoing clinical trial of ADI-PEG20, GEM, and DTX in sarcoma. CONCLUSIONS: The priming of tumors with ADI-PEG20 and DTX results in the stabilization of c-MYC potentiating the effect of GEM treatment via an increase in hENT1 expression. This finding is applicable to ASS1-deficient cancers that are currently treated with GEM.
doi: https://doi.org/10.1158/1078-0432.CCR-19-0206
- Advanced stage at diagnosis and elevated mortality among US patients with cancer infected with HIV in the National Cancer Data Base
Cancer 2019 Aug;125(16):2868-2876
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31050361
BACKGROUND: People living with HIV (PLWH) are at an increased risk of developing several cancers, but to the authors’ knowledge less is known regarding how HIV impacts the rate of progression to advanced cancer or death. METHODS: The authors compared stage of disease at the time of presentation and mortality after diagnosis between 14,453 PLWH and 6,368,126 HIV-uninfected patients diagnosed with cancers of the oral cavity, stomach, colorectum, anus, liver, pancreas, lung, female breast, cervix, prostate, bladder, kidney, and thyroid and melanoma using data from the National Cancer Data Base (2004-2014). Polytomous logistic regression and Cox proportional hazards regression were used to evaluate the association between HIV, cancer stage, and stage-adjusted mortality after diagnosis, respectively. Regression models accounted for the type of health facility at which cancer treatment was administered and the type of individual health insurance. RESULTS: HIV-infected patients with cancer were found to be more likely to be uninsured (HIV-infected: 5.0% vs HIV-uninfected: 3.3%; P < .0001) and were less likely to have private health insurance (25.4% vs 44.7%; P < .0001). Compared with those not infected with HIV, the odds of being diagnosed at an advanced stage of disease were significantly elevated in PLWH for melanoma and cancers of the oral cavity, liver, female breast, prostate, and thyroid (odds ratio for stage IV vs stage I range, 1.24-2.06). PLWH who were diagnosed with stage I to stage III disease experienced elevated mortality after diagnosis across 13 of the 14 cancer sites evaluated, with hazard ratios ranging from 1.20 (95% CI, 1.14-1.26) for lung cancer to 1.85 (95% CI, 1.68-2.04), 1.85 (95% CI, 1.51-2.27), and 2.93 (95% CI, 2.08-4.13), respectively, for cancers of the female breast, cervix, and thyroid. CONCLUSIONS: PLWH were more likely to be diagnosed with advanced-stage cancers and to experience elevated mortality after a cancer diagnosis, even after accounting for health care-related factors.
doi: https://doi.org/10.1002/cncr.32158
- Detection of NRG1 Gene Fusions in Solid Tumors
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Aug;25(16):4966-4972
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30988082
PURPOSE: NRG1 gene fusions are rare but potentially actionable oncogenic drivers that are present in some solid tumors. Details regarding the incidence of these gene rearrangements are lacking. Here, we assessed the incidence of NRG1 fusions across multiple tumor types and described fusion partners. EXPERIMENTAL DESIGN: Tumor specimens submitted for molecular profiling at a Clinical Laboratory Improvement Amendments (CLIA)-certified genomics laboratory and that underwent fusion testing by anchored multiplex PCR for targeted RNA sequencing were retrospectively identified. The overall and tumor-specific incidence was noted, as was the specific fusion partner. RESULTS: Out of 21,858 tumor specimens profiled from September 2015 to December 2018, 41 cases (0.2%) harbored an NRG1 fusion. Multiple fusion partners were identified. Fusion events were seen across tumor types. The greatest incidence was in non-small cell lung cancer (NSCLC, 25), though this represented only 0.3% of NSCLC cases tested. Other tumor types harboring an NRG1 fusion included gallbladder cancer, renal cell carcinoma, bladder cancer, ovarian cancer, pancreatic cancer, breast cancer, neuroendocrine tumor, sarcoma, and colorectal cancer. CONCLUSIONS: NRG1 fusions can be detected at a low incidence across multiple tumor types with significant heterogeneity in fusion partner.See related commentary by Dimou and Camidge, p. 4865.
doi: https://doi.org/10.1158/1078-0432.CCR-19-0160
- Design of an immunohistochemistry biomarker panel for diagnosis of pancreatic adenocarcinoma
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31445888
BACKGROUND: Challenges still exist in differentiating pancreatic adenocarcinoma from benign disease. The use of adjuvant testing of tissue biopsies has demonstrated potential diagnostic value. We designed a proof of concept study to first validate four individual immunohistochemistry biomarkers and then combine them into a panel to boost overall diagnostic sensitivity. METHODS: Malignant and benign pancreas from 27 pancreaticoduodenectomy specimens underwent immunohistochemistry staining with VHL, IMP3, S100A4, S100P. Using ROC curve analysis, threshold criteria for number of cells staining were chosen for each biomarker. Biomarkers were then evaluated as a panel for their ability to discriminate malignant from benign specimens. RESULTS: Diagnostic sensitivity of VHL, IMP3, S100A4, and S100P were 75.0%, 79.2%, 45.8%, and 0%. When VHL, IMP3, and S100A4 were grouped into a panel, they were able to distinguish cancer from normal tissue with a sensitivity of 100% and a specificity of 96%. CONCLUSIONS: The high diagnostic value of an IHC panel consisting of VHL, IMP3, and S100A4 on surgical specimens suggests the need for future prospective studies of these biomarkers on biopsy specimens.
doi: https://doi.org/10.1016/j.pan.2019.08.007
- Significance of Examined Lymph Node Number in Accurate Staging and Long-term Survival in Resected Stage I-II Pancreatic Cancer-More is Better? A Large International Population-based Cohort Study
Annals of surgery 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31425290
OBJECTIVE: This large international cohort study aimed to investigate the associations of examined lymph node (ELN) number with accurate staging and long-term survival in pancreatic adenocarcinoma (PaC) and to robustly determine the minimal and optimal ELN thresholds. SUMMARY BACKGROUND DATA: ELN number is an important quality metric in cancer care. The recommended minimal ELN number in PaC to accurately stage cancer varies greatly across guidelines, and the optimal number especially to adequately stratify patient survival has not yet been established. METHODS: Population-based data on patients with stage I to II PaC resected in 2003 to 2015 from the US Surveillance, Epidemiology, and End Results (SEER)-18 Program and Netherlands National Cancer Registry (NCR) were analyzed. Associations of ELN number with stage migration and survival were evaluated using multivariable-adjusted logistic and Cox regression models, respectively. The series of odds ratios (ORs) for negative-to-positive node stage migration and hazard ratios (HRs) for survival with more ELNs were fitted using a LOWESS smoother, and structural breakpoints were determined by Chow test. RESULTS: Overall 16,241 patients were analyzed. With increasing ELN number, both cohorts exhibited significant proportional increases from node-negative to node-positive disease [ORSEER-18=1.05, 95% confidence interval (CI) = 1.04-1.05; ORNCR = 1.10, 95% CI = 1.08-1.12] and serial improvements in survival (HRSEER-18 = 0.98, 95% CI = 0.98-0.99; HRNCR = 0.98, 95% CI = 0.97-0.99) per additional ELN after controlling for confounders. Associations for stage migration and survival remained significant in most stratifications by patient, tumor, and treatment factors. Cut-point analyses suggested a minimal threshold ELN number of 11 and an optimal number of 19, which were validated both internally in the derivative US cohort and externally in the Dutch cohort with the ability to well discriminate different probabilities of both survival and stage migration. CONCLUSIONS: In stage I to II PaC, more ELNs are associated with more precise nodal staging, which might largely explain the survival association. Our observational study does not suggest causality, and does not encourage more extended lymphadenectomy before further randomized evidence is obtained. Our results robustly conclude 11 ELNs as the minimal and suggest 19 ELNs as the optimal cut-points, for evaluating quality of lymph node examination and possibly for stratifying postoperative prognosis.
doi: https://doi.org/10.1097/SLA.0000000000003558
- Transgenic Expression of PRSS1R122H Sensitizes Mice to Pancreatitis
Gastroenterology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31419436
BACKGROUND & AIMS: Mutations in the trypsinogen gene (PRSS1) cause human hereditary pancreatitis. However, it is not clear how mutant forms of PRSS1 contribute to disease development. We studied the effects of expressing mutant forms of human PRSS1 in mice. METHODS: We expressed forms of PRSS1 with and without the mutation encoding R122H (PRSS1R122H) specifically in pancreatic acinar cells under control of a full-length pancreatic elastase gene promoter. Mice that did not express these transgenes were used as controls. Mice were given injections of caerulein to induce acute pancreatitis or injections of lipopolysaccharide (LPS) to induce chronic pancreatitis. Other groups of mice were fed ethanol or placed on a high-fat diet to induce pancreatitis. Pancreata were collected and analyzed by histology, immunoblots, real-time PCR, and immunohistochemistry. Trypsin enzymatic activity and chymotrypsin enzymatic activity were measured in pancreatic homogenates. Blood was collected and serum amylase activity was measured. RESULTS: Pancreata from mice expressing transgenes encoding PRSS1 or PRSS1R122H had focal areas of inflammation; these lesions were more prominent in mice that express PRSS1R122H. Pancreata from mice that express PRSS1 or PRSS1R122H had increased levels of HSP70 and NRF2 and reduced levels of chymotrypsin C (CTRC), compared with control mice. Increased expression of PRSS1 or PRSS1R122H increased focal damage in pancreatic tissues and increased the severity of acute pancreatitis after caerulein injection. Administration of LPS exacerbated inflammation in mice that express PRSS1R122H compared to mice that express PRSS1 or control mice. Mice that express PRSS1R122H developed more severe pancreatitis after ethanol feeding or a high-fat diet than mice that express PRSS1 or control mice. Pancreata from mice that express PRSS1R122H had more DNA damage, apoptosis, and collagen deposition and increased trypsin activity and infiltration by inflammatory cells than mice that express PRSS1 or control mice. CONCLUSIONS: Expression of a transgene encoding PRSS1R122H in mice promoted inflammation and increase the severity of pancreatitis, compared with mice that express PRSS1 or control mice. These mice might be used as a model for human hereditary pancreatitis and can be studied to determine mechanisms of induction of pancreatitis by LPS, ethanol, or a high-fat diet.
doi: https://doi.org/10.1053/j.gastro.2019.08.016
- Grading Pancreatic Neuroendocrine Tumors by Ki-67 Index Evaluated on Fine-Needle Aspiration Cell Block Material
American journal of clinical pathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31415691
OBJECTIVES: This study aimed to determine whether Ki-67 index evaluated on cytologic material could reliably grade pancreatic neuroendocrine tumors (PanNETs). METHODS: Cases with adequate cell block and available surgical specimens were included. Ki-67 index was calculated using “eyeballing,” “hot spot,” and “complete” counting methods. RESULTS: The overall concordance rates between cytology and surgical specimens were 71%, 73%, and 59%, respectively, by using eyeballing, hot spot, and complete counting approaches. All grade 1 tumors were correctly graded on cytology, but in grade 2 tumors concordance rates were only 36%, 41%, and 9%, respectively. All grade 2 tumors were undergraded when cell blocks contained fewer than 1,000 cells, while concordance rate increased to 57%, 64%, and 14%, respectively, in cases with 1,000 cells or more. CONCLUSIONS: Grade 2 PanNETs can be significantly undergraded when Ki-67 index is evaluated on cell block material. In cases with 1,000 or more cells, the hot spot counting method has better correlation with surgical specimens.
doi: https://doi.org/10.1093/ajcp/aqz110
- Randomized Comparison of Gastric Tube Reconstruction With and Without Duodenal Diversion Plus Roux-en-Y Anastomosis After Esophagectomy
Annals of surgery 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31415003
OBJECTIVE: This prospective randomized phase-II trial examined whether gastric reconstruction with duodenal diversion plus Roux-en-Y anastomosis(RY) minimized gastroduodenal reflux and delayed gastric emptying compared with standard gastric reconstruction. SUMMARY BACKGROUND DATA: There is no established standard surgical procedure to prevent both gastroduodenal reflux and delayed gastric emptying simultaneously. METHODS: Sixty patients with thoracic esophageal cancer scheduled to undergo esophagectomy with retrosternal gastric tube reconstruction were randomly allocated to standard gastric reconstruction (non-RY, n = 31) or gastric reconstruction with duodenal diversion plus RY (n = 29) groups. Primary endpoint was quality of life assessed by DAUGS-32 score 1 year after surgery. Secondary endpoints were the extent of postoperative duodenal juice reflux into the gastric tube, postoperative morbidity, endoscopic findings, body weight changes, and nutritional status. RESULTS: Preoperative clinicopathological characteristics and postoperative morbidity did not differ significantly between groups. However, operation time and blood loss volume were significantly higher in the RY group. Pancreatic amylase concentrations in the gastric conduit on postoperative days 2, 3, and 7 were higher in the non-RY group. Postoperative endoscopic examination showed residual gastric content in 7 of 17 patients in the non-RY group but in none in the RY group (P = 0.012). Quality of life was significantly favorable in the RY group with regard to reflux symptoms and food passage dysfunction. Postoperative body weight changes, serum albumin levels, and peripheral blood lymphocyte counts were not significantly different between groups. CONCLUSION: Gastric reconstruction with duodenal diversion plus RY is effective in improving both gastroduodenal reflux and delayed gastric emptying.
doi: https://doi.org/10.1097/SLA.0000000000003557
- Rosai-Dorfman Disease of the Digestive System-Beware Vasculopathy: A Clinicopathologic Analysis
The American journal of surgical pathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31414989
Rosai-Dorfman disease (RDD) is a rare non-Langerhans cell histiocytic proliferation that occurs in nodal and extranodal sites. Rare examples of the disease involving the digestive system have been described. To characterize the digestive tract manifestations of this disease, 12 specimens from 11 patients with extranodal RDD affecting the digestive organs were analyzed. Hematoxylin and eosin sections and available immunohistochemical stains were reviewed, and the clinical information was obtained from patients’ electronic or submitted records. Eight patients were female and 3 male (median age, 65 y; range, 17 to 76 y). Abdominal pain was the most frequent symptom. Six patients had an associated immunologic or malignant disease. Nine lesions arose in the gastrointestinal tract (1 involving the appendix, 2 right colon, 6 left colon), 2 in the pancreas, and 1 in the liver. Two patients had the coexistent nodal disease, and 1 had bone and soft-tissue involvement. The lesions were generally composed of polygonal to spindle-shaped histiocytes with eosinophilic to clear cytoplasm admixed with lymphoplasmacytic cells. The inflammatory cells formed lymphoid aggregates in 7 cases and included focally scattered or small collections of neutrophils in 6 cases. Fibrosis was variable, and 4 cases had a storiform pattern. Vasculopathy in the form of a thickened capillary wall, medium-sized arterial wall infiltration by lesional and inflammatory cells and phlebitis was seen in 10, 5, and 2 cases, respectively. All cases were reactive for S100-protein. Of the 5 patients with follow-up, 1 developed immunoglobulin A nephropathy and died of renal failure.
doi: https://doi.org/10.1097/PAS.0000000000001343
- Lipid droplet velocity is a microenvironmental sensor of aggressive tumors regulated by V-ATPase and PEDF
Laboratory investigation; a journal of technical methods and pathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31409893
Lipid droplets (LDs) utilize microtubules (MTs) to participate in intracellular trafficking of cargo proteins. Cancer cells accumulate LDs and acidify their tumor microenvironment (TME) by increasing the proton pump V-ATPase. However, it is not known whether these two metabolic changes are mechanistically related or influence LD movement. We postulated that LD density and velocity are progressively increased with tumor aggressiveness and are dependent on V-ATPase and the lipolysis regulator pigment epithelium-derived factor (PEDF). LD density was assessed in human prostate cancer (PCa) specimens across Gleason scores (GS) 6-8. LD distribution and velocity were analyzed in low and highly aggressive tumors using live-cell imaging and in cells exposed to low pH and/or treated with V-ATPase inhibitors. The MT network was disrupted and analyzed by α-tubulin staining. LD density positively correlated with advancing GS in human tumors. Acidification promoted peripheral localization and clustering of LDs. Highly aggressive prostate, breast, and pancreatic cell lines had significantly higher maximum LD velocity (LDVmax) than less aggressive and benign cells. LDVmax was MT-dependent and suppressed by blocking V-ATPase directly or indirectly with PEDF. Upon lowering pH, LDs moved to the cell periphery and carried metalloproteinases. These results suggest that acidification of the TME can alter intracellular LD movement and augment velocity in cancer. Restoration of PEDF or blockade of V-ATPase can normalize LD distribution and decrease velocity. This study identifies V-ATPase and PEDF as new modulators of LD trafficking in the cancer microenvironment.
doi: https://doi.org/10.1038/s41374-019-0296-8
- Mouse pancreatic ductal organoid culture as a relevant model to study exocrine pancreatic ion secretion
Laboratory investigation; a journal of technical methods and pathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31409889
Pancreatic exocrine secretory processes are challenging to investigate on primary epithelial cells. Pancreatic organoid cultures may help to overcome shortcomings of the current models, however the ion secretory processes in pancreatic organoids-and therefore their physiological relevance or their utility in disease modeling-are not known. To answer these questions, we provide side-by-side comparison of gene expression, morphology, and function of epithelial cells in primary isolated pancreatic ducts and organoids. We used mouse pancreatic ductal fragments for experiments or were grown in Matrigel to obtain organoid cultures. Using PCR analysis we showed that gene expression of ion channels and transporters remarkably overlap in primary ductal cells and organoids. Morphological analysis with scanning electron microscopy revealed that pancreatic organoids form polarized monolayers with brush border on the apical membrane. Whereas the expression and localization of key proteins involved in ductal secretion (cystic fibrosis transmembrane conductance regulator, Na+/H+ exchanger 1 and electrogenic Na+/HCO3- cotransporter 1) are equivalent to the primary ductal fragments. Measurements of intracellular pH and Cl- levels revealed no significant difference in the activities of the apical Cl-/HCO3- exchange, or in the basolateral Na+ dependent HCO3- uptake. In summary we found that ion transport activities in the mouse pancreatic organoids are remarkably similar to those observed in freshly isolated primary ductal fragments. These results suggest that organoids can be suitable and robust model to study pancreatic ductal epithelial ion transport in health and diseases and facilitate drug development for secretory pancreatic disorders like cystic fibrosis, or chronic pancreatitis.
doi: https://doi.org/10.1038/s41374-019-0300-3
- Dissecting the presence of malignant squamous cells in pancreatic cytopathology: A case series
Diagnostic cytopathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31407529
The presence of malignant squamous cells in pancreatic cytopathology is a rare phenomenon that results either from a primary or a metastatic process. Pancreatic adenosquamous carcinoma (PASC) represents the most common variant of pancreatic ductal adenocarcinoma and is associated with a dismal prognosis. Within the period of 2013-2018, the archives of “Hygeia and Mitera Hospital” were searched for pancreatic cytopathology-related diagnoses that included the interpretation of “malignant squamous cells present.” All fine needle aspirations (FNAs) of pancreatic lesions, including liver metastases in patients with known pancreatic primaries, were retrieved along with their relevant clinical information. Five pancreatic and two liver FNAs acquired from a total of six patients were reexamined. None of these patients had any documented history of primary squamous malignancy elsewhere. All pancreatic and one of the two liver FNAs showed malignant squamous cells, identified based on either morphology or immunochemistry. The other liver FNA represented a metastatic deposit which comprised of only a glandular component, whereas the associated pancreatic FNA exhibited both squamous and glandular counterparts. Most cases characteristically showed necrosis and keratinization. Of interest, two cases revealed the presence of tumor-associated giant cells. In conclusion, the presence of malignant squamous cells in pancreatic FNAs could mean the presence of PASC, especially when there is no documented history of a primary malignancy and a complete clinical and imaging workup has been performed. Immunochemistry on cell block material could help to confirm squamous differentiation in the absence of overt keratinization.
doi: https://doi.org/10.1002/dc.24302
- Laparoscopic Suprapancreatic Lymph Node Dissection Using a Systematic Mesogastric Excision Concept for Gastric Cancer
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31407184
BACKGROUND: Gastrointestinal cancer surgery requires en bloc removal of the primary tumor and organ-specific mesentery1,2. However, this surgical concept for gastric cancer has not yet been applied because of the morphological complexity of the mesenteries of the stomach. Lymph node dissection in gastric cancer surgery can be roughly performed into three regions: lesser curvature, grater curvature, and suprapancreatic region. In this video, we introduced laparoscopic lymphadenectomy in the suprapancreatic region using a systematic mesogastric excision (SME), which has been reported as a concept to perform en bloc resection3. METHODS: This procedure was divided into three steps. First, mesenterization of the mesogastrium was performed by dissecting the embryological planes, and the mesogastrium was dissected from the retroperitoneal surface (Fig. 1a). Second, soft tissue, including the lymph node, was separated from the pancreas and the splenic artery by tracing the inner dissectable layer (Fig. 1b). Finally, the tumor-specific mesentery was transected according to the extent of the lymphadenectomy (Fig. 1c). Fig. 1 Intraoperative findings during the stepwise procedure in dissecting the lymph node in the suprapancreatic region. The red broken line indicates the surgical outline. a The mesogastrium is dissected from the retroperitoneal tissue. b The mesogastrium is separated from the pancreas and splenic artery. c The mesogastric transection line is determined on the basis of the extent of the lymphadenectomy. Inf. phrenic a. inferior phrenic artery; PGA posterior gastric artery; Post. epiploic a. posterior epiploic artery; RV renal vein; SA splenic artery; SV splenic vein RESULTS: Between January 2017 and December 2017, six patients underwent laparoscopic distal gastrectomy with D2 lymphadenectomy using SME. The median time required to complete the suprapancreatic lymphadenectomy was 48 min. No patient underwent conversion to open surgery or experienced intraoperative complications. CONCLUSIONS: We believe that this laparoscopic suprapancreatic lymphadenectomy using SME takes advantage of the surgical anatomy and achieves en bloc removal of the primary tumor and gastric mesentery. This series is a proof of concept that this procedure can be performed in a timely manner and is feasible.
doi: https://doi.org/10.1245/s10434-019-07700-5
- Extended Laparoscopic Central Pancreatectomy with Clamping of the Mesentericoportal Vein and Resection of the Splenic Vessels for a Large Solid Pseudopapillary Tumor
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31407182
BACKGROUND: Solid pseudopapillary tumors (SPPTs) are low malignant potential entities found mainly in young females.1,2 Pancreatectomy without tumor rupture is the treatment of choice, and the laparoscopic approach is indicated.3,4 Limited pancreatectomy is possible due to the low risk of malignancy (< 10%) based on the low risk of lymph node invasion or true vascular invasion.1,2 Centrally located large SPPTs can be treated by extended central pancreatectomy with or without vascular resection to avoid pancreatoduodenectomy or distal pancreatectomy. METHODS: A 24-year-old woman was admitted with abdominal pain. A 6-cm SPPT was discovered at the neck-body junction in close contact with the anterior aspect of the mesentericoportal vein (MPV) and the splenic vessels, with signs of segmental portal hypertension. To avoid an extended pancreatectomy for this young patient, an extended central pancreatectomy was performed, with resection of the splenic vessels, and the MPV was freed from the tumor under clamping for 10 min, with no need for vascular reconstruction. The duration of the surgery was 260 min, with 200 ml of blood loss and no transfusion. RESULTS: The woman’s postoperative course was uneventful, with a hospital stay of 16 days. Histology confirmed the diagnosis of a 6-cm SPPT tumor (R0 and N0). The patient was asymptomatic 1 year later, with no tumor recurrence and no pancreatic insufficiency. Between 2011 and 2018 the authors performed 72 laparoscopic central pancreatectomies, with SPPT performed for 13 patients (18%). Laparoscopic central pancreatectomy was extended (n = 5) or standard (n = 8) with no conversion, no recurrence, and no pancreatic insufficiency. CONCLUSION: An SPPT tumor is a good indication for the laparoscopic approach because this entity is found in young patients with a low risk of malignancy. Large centrally located tumors can be treated by extended central pancreatectomy to avoid a large pancreatectomy with greater early and long-term disadvantages.
doi: https://doi.org/10.1245/s10434-019-07689-x
- Robotic Extended Right Hemicolectomy with Complete Mesocolic Excision and D3 Lymph Node Dissection
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31407176
BACKGROUND: Recent studies have shown the benefits of complete mesocolic excision and extended lymphadenectomy (D3 lymph node dissection) in patients with colon cancer.1-3 METHODS: We present the case of a 62-year-old male with hepatic flexure adenocarcinoma. No metastatic disease was identified by computed tomography. A robot-assisted extended right hemicolectomy with complete mesocolic excision, D3 lymph node dissection, and resection of the mesentery with intact visceral peritoneum was performed. RESULTS: The trocars are placed in the right lower (8 mm), lower midline (8 mm), and left upper (12 mm) quadrants. The camera port is placed superior to the umbilicus, and the assistant port is placed in the left lower quadrant. The robotic right lower port is used to place the cecum on tension in order to outline the ileocolic pedicle. The assistant retracts the transverse colon cephalad to outline the superior mesenteric artery and vein. Using two robotic arms, the surgeon begins dissection over the superior mesenteric vein inferior to the ileocolic pedicle. Cephalad dissection along the superior mesenteric vein proceeds with reflection of the mesentery and D3 lymph nodes laterally to allow en bloc resection. The ileocolic and middle colic vessels are identified, ligated and divided at their origins. The plane is then developed between the right colon mesentery and the retroperitoneum, including Gerota’s fascia, duodenum, and head of the pancreas, in a medial-to-lateral fashion, with care taken to ensure an intact visceral peritoneum is maintained. The proximal transverse colon, hepatic flexure, and ascending colon are mobilized by taking down lateral attachments. The intervening mesentery is transected, and perfusion is assessed with indocyanine green fluorescence imaging. An intracorporeal, isoperistaltic, side-to-side anastomosis is performed using the 45-mm robotic stapler. The common enterotomy is sewn closed in two layers. Pathology showed T3N0 adenocarcinoma with all negative margins. CONCLUSION: Extended right hemicolectomy with complete mesocolic excision and D3 lymph node dissection is facilitated by a robotic approach, which improves visualization and instrument dexterity.
doi: https://doi.org/10.1245/s10434-019-07692-2
- Short-Term Outcomes of Laparoscopic and Open Total Gastrectomy for Gastric Cancer: A Nationwide Retrospective Cohort Analysis
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31407172
BACKGROUND: Laparoscopic total gastrectomy is gradually gaining popularity; however, previous studies have produced conflicting results regarding the safety and advantages of the procedure, partly because of small sample sizes. The purpose of this study was to compare short-term outcomes between laparoscopic and open total gastrectomy for gastric cancer. METHODS: We analyzed data for patients undergoing laparoscopic or open total gastrectomy for clinical stage I-III gastric cancer from July 2010 to March 2017, using a Japanese nationwide inpatient database. We performed propensity-matched analyses to compare in-hospital mortality, morbidity, duration of anesthesia, time to first oral intake, and length of postoperative stay between the two groups. RESULTS: Among 58,689 eligible patients, propensity-score matching created 12,229 pairs. Laparoscopic total gastrectomy was associated with higher incidences of anastomotic leakage (2.9% vs. 1.7%, p < 0.001) and stenosis (0.9% vs. 0.6%, p = 0.02), lower incidences of pancreatic injury (1.4% vs. 1.8%, p = 0.01), endoscopic hemostasis (0.9% vs. 1.7%, p < 0.001), blood transfusion (9.9% vs. 17.7%, p < 0.001) and 30-day readmission, a shorter interval from surgery to first oral intake (4 vs. 5 days, p < 0.001), shorter postoperative hospital stay (14 vs. 15 days, p < 0.001), and a longer duration of anesthesia (323 vs. 304 min, p < 0.001). There was no significant difference in in-hospital mortality (0.6% vs. 0.8%, p = 0.58). CONCLUSIONS: Laparoscopic total gastrectomy has some advantages over open surgery for gastric cancer in terms of time to first oral intake and postoperative length of stay, but the incidence of anastomotic leakage was higher than that of open total gastrectomy.
doi: https://doi.org/10.1245/s10434-019-07688-y
- Disruption of IRE1α through its kinase domain attenuates multiple myeloma
Proceedings of the National Academy of Sciences of the United States of America 2019 Aug;116(33):16420-16429
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31371506
Multiple myeloma (MM) arises from malignant immunoglobulin (Ig)-secreting plasma cells and remains an incurable, often lethal disease despite therapeutic advances. The unfolded-protein response sensor IRE1α supports protein secretion by deploying a kinase-endoribonuclease module to activate the transcription factor XBP1s. MM cells may co-opt the IRE1α-XBP1s pathway; however, the validity of IRE1α as a potential MM therapeutic target is controversial. Genetic disruption of IRE1α or XBP1s, or pharmacologic IRE1α kinase inhibition, attenuated subcutaneous or orthometastatic growth of MM tumors in mice and augmented efficacy of two established frontline antimyeloma agents, bortezomib and lenalidomide. Mechanistically, IRE1α perturbation inhibited expression of key components of the endoplasmic reticulum-associated degradation machinery, as well as secretion of Ig light chains and of cytokines and chemokines known to promote MM growth. Selective IRE1α kinase inhibition reduced viability of CD138+ plasma cells while sparing CD138- cells derived from bone marrows of newly diagnosed or posttreatment-relapsed MM patients, in both US- and European Union-based cohorts. Effective IRE1α inhibition preserved glucose-induced insulin secretion by pancreatic microislets and viability of primary hepatocytes in vitro, as well as normal tissue homeostasis in mice. These results establish a strong rationale for developing kinase-directed inhibitors of IRE1α for MM therapy.
doi: https://doi.org/10.1073/pnas.1906999116
- Mild maternal hyperglycemia in INSC93S transgenic pigs causes impaired glucose tolerance and metabolic alterations in neonatal offspring
Disease models & mechanisms 2019 Aug;12(8):
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31308048
Alongside the obesity epidemic, the prevalence of maternal diabetes is rising worldwide, and adverse effects on fetal development and metabolic disturbances in the offspring’s later life have been described. To clarify whether metabolic programming effects are due to mild maternal hyperglycemia without confounding obesity, we investigated wild-type offspring of INSC93S transgenic pigs, which are a novel genetically modified large-animal model expressing mutant insulin (INS) C93S in pancreatic β-cells. This mutation results in impaired glucose tolerance, mild fasting hyperglycemia and insulin resistance during late pregnancy. Compared with offspring from wild-type sows, piglets from hyperglycemic mothers showed impaired glucose tolerance and insulin resistance (homeostatic model assessment of insulin resistance: +3-fold in males; +4.4-fold in females) prior to colostrum uptake. Targeted metabolomics in the fasting and insulin-stimulated state revealed distinct alterations in the plasma metabolic profile of piglets from hyperglycemic mothers. They showed increased levels of acylcarnitines, gluconeogenic precursors such as alanine, phospholipids (in particular lyso-phosphatidylcholines) and α-aminoadipic acid, a potential biomarker for type 2 diabetes. These observations indicate that mild gestational hyperglycemia can cause impaired glucose tolerance, insulin resistance and associated metabolic alterations in neonatal offspring of a large-animal model born at a developmental maturation status comparable to human babies.
doi: https://doi.org/10.1242/dmm.039156
- Long-term outcomes of therapeutic ERCP in pediatric patients with pancreas divisum presenting with acute recurrent or chronic pancreatitis
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31421974
OBJECTIVES: The aim of this study was to evaluate the long-term outcomes of therapeutic endoscopic retrograde cholangiopancreatography (ERCP) for pediatric patients with pancreas divisum (PD) presenting with acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP). METHODS: Between May 2008 and August 2017, pediatric patients with PD who received endotherapy at Ruijin Hospital were identified and grouped according to clinical presentation, namely ARP and CP. Primary success was defined as patients’ improvement in symptoms after index ERCPs, without further intervention or any analgesic. RESULTS: A total of 74 ERCPs were performed in 38 pediatric patients. The frequency of at least 1 genetic mutation identified in patients with ARP and CP was 44.4% and 68.4%, respectively. Patients with CP required more ERCPs than those with ARP (2.4 ± 1.7 vs. 1.1 ± 0.4, P = 0.005). The incidence of post-ERCP complications was 14.9%, including pancreatitis of 13.5% and hemorrhage of 1.4%. During a median follow-up duration of 41 months (range, 12-123 months), the frequency of pancreatitis episodes decreased significantly from 2.31 to 0.45 (P < 0.0001). The 25% recurrence and reintervention rates were estimated at 25 and 48 months, respectively, without significant difference between patients with ARP or CP. There was a nonsignificant trend towards a higher rate of primary success in patients with ARP than those with CP (92.9% vs. 69.6%, P = 0.123). After further endotherapy, 91.3% patients with CP improved clinically. CONCLUSIONS: Therapeutic ERCP is an effective and safe intervention for pediatric patients with symptomatic PD. Patients presenting with CP seem to achieve improvement after additional ERCPs.
doi: https://doi.org/10.1016/j.pan.2019.08.004
- Prognostic significance of neutrophil-lymphocyte ratio in resectable pancreatic neuroendocrine tumors with special reference to tumor-associated macrophages
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31409525
BACKGROUND: Recent studies have shown that the systemic inflammatory response induced by cancer leads to cancer progression. Neutrophil-to-lymphocyte ratio (NLR) is the most reliable marker to detect systemic inflammation. In this study, we investigated the significance of NLR in patients with well-differentiated pancreatic neuroendocrine tumors (PanNETs) according to the World Health Organization 2017 classification. METHODS: We retrospectively collected data for patients with PanNET who underwent pancreatic resection with curative intent between January 2008 and December 2017 at six institutions. Clinicopathological factors, recurrence, and immunohistochemical staining of tumor-associated macrophages (TAMs) were analyzed in a total of 55 patients in this study. RESULTS: High NLR (>3.41) in patients was significantly associated with higher white blood cell count, higher Ki-67 index, higher mitotic count, higher grade, higher incidence of lymph node metastasis, higher incidence of lymphatic and neural invasion, massive blood loss, and a large number of CD163-expressing TAMs. Recurrence-free survival of patients with high NLR was significantly poorer than that of patients with low NLR. Multivariate analysis identified high NLR, NET Grade 2 (G2) or Grade 3 (G3), and synchronous hepatic resection as independent risk factors for recurrence after curative resection. CONCLUSIONS: NLR is a promising predictor of recurrence after pancreatectomy that needs to be further investigated and that accumulation of TAMs in the tumor could be one of the causes of NLR elevation.
doi: https://doi.org/10.1016/j.pan.2019.08.003
- Pancreas FNA
Cytopathology : official journal of the British Society for Clinical Cytology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31400170
67-year-old lady diagnosed with right breast invasive ductal carcinoma with axillary node involvement. Staging FDG PET identified a small enhancing 1.2cm ‘indeterminate’ nodule within pancreatic tail, which CT pancreas with contrast revealed to be hypervascular. This article is protected by copyright. All rights reserved.
doi: https://doi.org/10.1111/cyt.12767
- Comparison of Tissue and Blood Concentrations of Oxaliplatin Administrated by Different Modalities of Intraperitoneal Chemotherapy
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31399820
BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new technology for delivering intraperitoneal chemotherapy. It is generally assumed that with PIPAC, the ratio of peritoneal to systemic drug concentration is superior to liquid hyperthermic intraperitoneal chemotherapy (HIPEC). To date, no direct comparative data are available supporting such an assumption. MATERIALS AND METHODS: Twelve 65-day-old pigs were randomly separated into three groups of four pigs each, all of which received intraperitoneal chemotherapy using the following administration methods: PIPAC with oxaliplatin 92 mg in 150 ml dextrose 5% (Group 1); PIPAC with electrostatic aerosol precipitation (ePIPAC; Group 2); or laparoscopic HIPEC (L-HIPEC) with oxaliplatin 400 mg in 4 L dextrose 5% at 42 °C (Group 3). Serial blood and peritoneal tissue concentrations of oxaliplatin were determined by spectrometry. RESULTS: In all three groups, the maximum concentration of oxaliplatin in blood was detected 50-60 min after onset of the chemotherapy experiments, with no significant differences among the three groups (p = 0.7994). Blood oxaliplatin concentrations (0-30 min) were significantly higher in the L-HIPEC group compared with the ePIPAC group (p < 0.05). No difference was found for the overall systemic oxaliplatin absorption (area under the curve). Overall concentrations in the peritoneum were not different among the three groups (p = 0.4725), but were significantly higher in the visceral peritoneum in the PIPAC group (p = 0.0242). CONCLUSIONS: Blood and tissue concentrations were comparable between all groups; however, depending on the intraperitoneal area examined and the time points of drug delivery, the concentrations differed significantly between the three groups.
doi: https://doi.org/10.1245/s10434-019-07695-z
- Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes
Cell 2019 Aug;178(4):795-806.e12
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31398337
Most patients diagnosed with resected pancreatic adenocarcinoma (PDAC) survive less than 5 years, but a minor subset survives longer. Here, we dissect the role of the tumor microbiota and the immune system in influencing long-term survival. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition in PDAC patients with short-term survival (STS) and long-term survival (LTS). We found higher alpha-diversity in the tumor microbiome of LTS patients and identified an intra-tumoral microbiome signature (Pseudoxanthomonas-Streptomyces-Saccharopolyspora-Bacillus clausii) highly predictive of long-term survivorship in both discovery and validation cohorts. Through human-into-mice fecal microbiota transplantation (FMT) experiments from STS, LTS, or control donors, we were able to differentially modulate the tumor microbiome and affect tumor growth as well as tumor immune infiltration. Our study demonstrates that PDAC microbiome composition, which cross-talks to the gut microbiome, influences the host immune response and natural history of the disease.
doi: https://doi.org/10.1016/j.cell.2019.07.008
- Comparison of overall survival and perioperative outcomes of laparoscopic pancreaticoduodenectomy and open pancreaticoduodenectomy for pancreatic ductal adenocarcinoma: a systematic review and meta-analysis
BMC cancer 2019 Aug;19(1):781
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31391085
BACKGROUND: The aim of this study was to compare the oncological outcomes and clinical efficacy of laparoscopic pancreaticoduodenectomy (LPD) and open pancreaticoduodenectomy (OPD) in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: We systematically searched PubMed, EMBASE, Web of Science, ClinicalTrials.gov and the Cochrane Central Register for studies published between May 1998 and May 2018. The included studies compared LPD and OPD for the treatment of PDAC. The oncological outcomes and perioperative data were analyzed. RESULTS: Eight studies involving 15,278 patients were included in our meta-analysis. No significant difference was found in the 5-year overall survival (OS) between patients undergoing the two types of surgery (HR: 0.97, 95% CI 0.82-1.15, p = 0.76). LPD resulted in a higher rate of R0 resection than OPD (OR: 1.16, 95% CI 0.85-1.57, p > 0.05). This study showed that compared with OPD, LPD resulted in comparable rates of postoperative pancreatic fistulas (POPFs) (OR: 1.07, 95% CI: 0.68-1.68, p = 0.77) and postoperative hemorrhage (OR: 1.74, 95% CI 0.96-3.71, p = 0.07), more harvested lymph nodes (WMD: 1.84, 95% CI: 0.95-2.72, p < 0.05), shorter hospital stays (WMD: -2.45, 95% CI: - 3.33- -1.56, p < 0.05), and less estimated blood loss (WMD: -374.30, 95% CI: - 513.06- -235.54, p < 0.05). CONCLUSIONS: LPD is equivalent to OPD with respect to 5-year OS and results in better perioperative clinical outcomes for patients with PDAC.
doi: https://doi.org/10.1186/s12885-019-6001-x
- A 12-year trend analysis of the incidence of gastrointestinal cancers in East Azerbaijan: last updated results of an ongoing population-based cancer registry
BMC cancer 2019 Aug;19(1):782
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31391032
BACKGROUND: The most recent results of Global Cancer Statistics indicated that gastrointestinal cancers, including gastric, colorectal, esophageal, and liver cancers, are among the most commonly diagnosed cancers worldwide. Previous reports from cancer registries in East Azerbaijan have shown that there is a high incidence of gastrointestinal cancer in this region, so we performed a trend analysis to determine the pattern of change over the last decade. METHODS: In total, 12 years of cancer registry data were collected from different sources in East Azerbaijan, and a data quality check was performed to ensure clean data. Using the 2000 World Health Organization standard population, we then generated age-standardized incidence rates (ASRs) for different cancers, and for each year from 1383 to 1394 of the Persian calendar (i.e., 19 March 2004 to 20 March 2015). Annual percent changes (APCs) and Average annual percent changes (AAPCs) in the ASRs for esophageal, gastric, small intestine, colorectal, anal, liver, gallbladder, and pancreatic cancers were calculated using Joinpoint Software (Version 4.5.0.1, June 2017). RESULTS: An increase in most types of cancer was observed during the study period. The ASR for colorectal cancer increased from 2.9 to 13.6 per 100,000 women (APC, 9.7%) and from 2.2 to 17.8 per 100,000 men (APC, 10.2%). The ASR for gastric cancer showed a slight increasing trend from 10.5 to 13.5 per 100,000 women (APC, 1.3%) and from 3.1 to 29.9 per 100,000 men (APC, 3.2%). However, trend analysis showed a decreasing pattern for the ASR of esophageal cancer in both genders (APC,- 3%), with APCs of - 1.1% in females and - 0.4% in males. CONCLUSIONS: The latest results of the East Azerbaijan Population-Based Cancer Registry indicate that gastrointestinal cancers remain common, with significant increasing trends in their ASRs. Improved screening and early detection are needed in this region.
doi: https://doi.org/10.1186/s12885-019-6008-3
- The prognostic value of lncRNA SNHG1 in cancer patients: a meta-analysis
BMC cancer 2019 Aug;19(1):780
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31391030
BACKGROUND: Increasing evidence revealed that high expression level of lncRNA SNHG1 was associated with the unfavorable prognosis of cancer and maybe used as a valuable biomarker for cancer patients. The present meta->analysis is to analyze existing data to reveal potential clinical application of SNHG1 on cancer prognosis and tumor progression. All of the included studies were collected through a variety of retrieval strategies. And the articles were qualified by MOOSE and PRISMA checklists. METHODS: Up to Mar 20, 2018, literature collection was performed by comprehensive search through electronic databases, including the Cochrane library, PubMed, Embase, Web of science, Springer, Science direct, and three Chinese databases: CNKI, Weipu, and Wanfang. We analyzed 14 studies that met the criteria, and concluded that the increased SHNG1 level was correlated with poor OS and tumor progression. RESULTS: The combined results indicated that elevated SNHG1 expression level was significantly associated with poor OS (HR = 2.06, 95% CI: 1.69-2.52, P < 0.01) and PFS (HR = 2.78, 95% CI: 1.69-4.55, P < 0.01) in various cancers. Moreover, the promoted SNHG1 expression was also associated with tumor progression ((III/IV vs. I/II: HR = 1.89, 95% CI: 1.53-2.34, P < 0.01). In stratified analyses, a significantly unfavorable association of elevated lncRNA SNHG1 and OS was observed in both digestive system (HR = 2.04, 95% CI: 1.56-2.68, P < 0.01) and non-digestive system (HR = 2.09, 95% CI: 1.55-2.83, P < 0.01) cancer patients. CONCLUSIONS: The present analysis indicated that the increased SNHG1 is associated with poor OS in patients with general tumors and may be served as a useful prognostic biomarker.
doi: https://doi.org/10.1186/s12885-019-5987-4
- Dynamic serum alkaline phosphatase is an indicator of overall survival in pancreatic cancer
BMC cancer 2019 Aug;19(1):785
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31391026
BACKGROUND: The prognostic role of serum alkaline phosphatase (ALP) has been found in several kinds of solid malignant tumor, but has never been extensively discussed in pancreatic cancer, especially through the application of dynamic survival model which incorporates the varying nature of ALP measurements. METHODS: We conducted a retrospective study which successfully collected 551 histopathologically confirmed pancreatic ductal adenocarcinoma (PDAC) patients from a cancer specialized hospital in southwest China. The association between variant ALP which measured during the whole survival period and the overall survival (OS) of PDAC patients was evaluated by using dynamic Anderson-Gill (AG) model. Exhaustive sensitivity analysis was performed by adopting continuous cut-offs of ALP. RESULTS: After adjusted for possible confounding of serum albumin, total bilirubin and leukocyte counts, AG model revealed that, serum ALP during the survival period was nonlinearly associated with the OS of PDAC: for resected patients, compared with those whose ALP results ranged within the first quartile (<P25), patients whose ALP measurements belonged to the second (P25-P50), the third (P50-P75), and the forth (>P75) quartiles were observed 1.14 (95% CI: 0.29-4.56), 3.93 (95% CI: 1.23-12.60), 3.87 (95% CI: 1.32-11.36) folds of death hazard; whereas in un-resected PDAC patients, the hazard ratios (HRs) were 1.15 (95% CI: 0.79-1.68), 1.92 (95% CI: 1.32-2.78), and 1.97 (95% CI: 1.30-2.98), respectively. Sensitivity analysis revealed that, for both resected and un-resected patients, the results of AG model were robust with regard to various cut-offs of ALP, and an increased ALP was in general associated with significantly increased hazard of death. CONCLUSION: Serum ALP during the survival period was significantly associated with the OS of PDAC patients, especially for resected early stage PDAC patients. Future studies with expanded sample size and refined prospective design should be implemented to corroborate our major findings. Besides, the underlying mechanism for this possible hazardous role of ALP should also be investigated.
doi: https://doi.org/10.1186/s12885-019-6004-7
- Sclerosing epithelioid mesenchymal neoplasm of the pancreas - a proposed new entity
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31383964
We have encountered pancreatic tumors with unique histologic features, which do not conform to any of the known tumors of the pancreas or other anatomical sites. We aimed to define their clinicopathologic features and whether they are characterized by recurrent molecular signatures. Eight cases were identified; studied histologically and by immunohistochemistry. Selected cases were also subjected to whole-exome sequencing (WES; n = 4), RNA-sequencing (n = 6), Archer FusionPlex assay (n = 5), methylation profiling using the Illumina MethylationEPIC (850k) array platform (n = 6), and TERT promoter sequencing (n = 5). Six neoplasms occurred in females. The mean age was 43 years (range: 26-75). Five occurred in the head/neck of the pancreas. All patients were treated surgically; none received neoadjuvant/adjuvant therapy. All patients are free of disease after 53 months of median follow-up (range: 8-94). The tumors were well-circumscribed, and the median size was 1.8 cm (range: 1.3-5.8). Microscopically, the unencapsulated tumors had a geographic pattern of epithelioid cell nests alternating with spindle cell fascicles. Some areas showed dense fibrosis, in which enmeshed tumor cells imparted a slit-like pattern. The predominant epithelioid cells had scant cytoplasm and round-oval nuclei with open chromatin. The spindle cells displayed irregular, hyperchromatic nuclei. Mitoses were rare. No lymph node metastases were identified. All tumors were positive for vimentin, CD99 and cytokeratin (patchy), while negative for markers of solid pseudopapillary neoplasm, neuroendocrine, acinar, myogenic/rhabdoid, vascular, melanocytic, or lymphoid differentiation, gastrointestinal stromal tumor as well as MUC4. Whole-exome sequencing revealed no recurrent somatic mutations or amplifications/homozygous deletions in any known oncogenes or tumor suppressor genes. RNA-sequencing and the Archer FusionPlex assay did not detect any recurrent likely pathogenic gene fusions. Single sample gene set enrichment analysis revealed that these tumors display a likely mesenchymal transcriptomic program. Unsupervised analysis (t-SNE) of their methylation profiles against a set of different mesenchymal neoplasms demonstrated a distinct methylation pattern. Here, we describe pancreatic neoplasms with unique morphologic/immunophenotypic features and a distinct methylation pattern, along with a lack of abnormalities in any of key genetic drivers, supporting that these neoplasms represent a novel entity with an indolent clinical course. Given their mesenchymal transcriptomic features, we propose the designation of “sclerosing epithelioid mesenchymal neoplasm” of the pancreas.
doi: https://doi.org/10.1038/s41379-019-0334-5
- Pancreatic cancer-A disease in need: Optimizing and integrating supportive care
Cancer 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31381149
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that continues to be challenging to treat. PDAC has the lowest 5-year relative survival rate compared with all other solid tumor malignancies and is expected to become the second-leading cause of cancer-related death in the United States by 2030. Given the high mortality, there is an increasing role for concurrent anticancer and supportive care in the management of patients with PDAC with the aims of maximizing length of life, quality of life, and symptom control. Emerging trends in supportive care that can be integrated into the clinical management of patients with PDAC include standardized supportive care screening, early integration of supportive care into routine cancer care, early implementation of outpatient-based advance care planning, and utilization of electronic patient-reported outcomes for improved symptom management and quality of life. The most common symptoms experienced are nausea, constipation, weight loss, diarrhea, anorexia, and abdominal and back pain. This review article includes current supportive management strategies for these and others. Common disease-related complications include biliary and duodenal obstruction requiring endoscopic procedures and venous thromboembolic events. Patients with PDAC continue to have a poor prognosis. Systemic therapy options are able to palliate the high symptom burden but have a modest impact on overall survival. Early integration of supportive care can lead to improved outcomes.
doi: https://doi.org/10.1002/cncr.32423
- ESWL for large pancreatic calculi: Report of over 5000 patients
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31447280
INTRODUCTION: The primary aim of this study was to evaluate efficacy, safety and short-term pain relief after ESWL for large pancreatic calculi in over 5000 patients at a single center. METHODS: This is a retrospective analysis of prospectively collected data. Patients with painful calculi >5 mm, located in the head, neck and body region in the MPD, who were not amenable for extraction by the standard procedure of endoscopic pancreatic sphincterotomy were subjected to ESWL using a third generation dual focus lithotripter. Patients were followed up at 6 months for outcome evaluation. RESULTS: A total of 5124 patients (66% males) were subjected to ESWL. Majority of stones (79.2%) were radiopaque. Single calculi were seen in 3851 (75.1%).The majority of stones were located in head region of MPD in 2824 (55.1%) patients. 4386 (85.5%) patients required 3 or less sessions for fragmentation and complete stone clearance was achieved in 3722 (72.6%). EPS was performed in 5022 (98%) while PD stenting was required in 3536 (69%) patients. Of the 4280 patients followed up for 6 months, 3529 (82.6%) patients were pain free. Another 512 (11.9%) patients had significant reduction in VAS score. In 229 (5.3%) there was no decrease in pain intensity. Minor and self-limiting complications were reported in 1153 (22.5%). DISCUSSION: Our study confirms the safety and efficacy and short-term pain relief of ESWL for large calculi in the MPD. In properly selected patients, this should be offered as the first line of therapy for all large MPD calculi not amenable to the standard techniques of stone extraction.
doi: https://doi.org/10.1016/j.pan.2019.08.001
- Variation in use of open and laparoscopic distal pancreatectomy and associated outcome metrics in a universal health care system
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31395453
BACKGROUND: Universal health care (UHC) should ensure equal access to and use of surgery, but few studies have explored variation in UHC systems. The objective was to describe practice of distal pancreatectomy in Norway covered exclusively by an UHC. METHODS: Data on all patients undergoing distal pancreatectomy from the Norwegian Patient Register over a 5-year period. Age- and gender-adjusted population-based resection rates (adj. per million/yr) for distal pancreatectomy were analysed across 4 regions and outcomes related to splenic salvage rate, hospital stay, reoperation, readmissions and 90-day mortality risk between regions. Risk is reported as odds ratio (OR) with 95% confidence interval (c.i.). RESULTS: Regional difference exist in terms of absolute numbers, with the majority of procedures done in one region (n = 331; 59.7%). Regional variation persisted for age- and gender-adjusted population-rates, with highest rate at 23.8/million/yr and lowest rate at 13.5/mill/yr (for a 176% relative difference; or an absolute difference of +10.3 resections/million/yr). Overall, a lapDP instead of an open DP was 3.5 times more likely in SouthEast compared to all other regions combined (lapDP rate: 83% vrs 24%, respectively; OR 15.4, 95% c.i. 10.1-23.5; P < 0.001). The splenic salvage rate was lower in SouthEast (19.9%) compared to all other regions (average 26.5%; highest in Central-region at 37.0%; P = 0.010 for trend). Controlled for other factors in multivariate regression, ‘region’ of surgery remained significantly associated with laparoscopic access. CONCLUSION: Despite a universal health care system, considerable variation exists in resection rates, use of laparoscopy and splenic salvage rates across regions.
doi: https://doi.org/10.1016/j.pan.2019.07.047
- Corrigendum to “Cystic pancreatic neuroendocrine tumors: A more favorable lesion?” [Pancreatology 19 (2) (March 2019) 372-376]
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31387834
doi: https://doi.org/10.1016/j.pan.2019.07.043
- Classification of Complication Clusters Might Vary in Different Populations With Chronic Pancreatitis
The American journal of gastroenterology 2019 Aug;114(8):1351-1352
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31386633
doi: https://doi.org/10.14309/ajg.0000000000000292
- The Impact of Dedicated Cancer Centers on Outcomes Among Medicare Beneficiaries Undergoing Liver and Pancreatic Cancer Surgery
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31376033
BACKGROUND: The Alliance of Dedicated Cancer Centers (DCCs) is comprised of 11 institutions that are exempt from the prospective payment system utilized by Medicare for hospital reimbursement. OBJECTIVE: The aim of this study was to compare short- and long-term outcomes of patients undergoing liver and pancreatic surgery for cancer at DCCs versus non-DCCs. METHODS: Patients who underwent a liver or pancreatic operation for a malignant indication between 2013 and 2015 were identified using the Medicare Inpatient Standard Analytic Files. Regression analyses and the Kaplan-Meier method were used to assess short- and long-term outcomes of patients at DCCs versus non-DCCs. RESULTS: Among 13,256 patients, 7.0% of patients were treated at a DCC. Median patient age and complexity of surgical procedures were comparable among DCCs and non-DCCs (all p > 0.05). Overall complications (16.5% vs. 23.6%), 90-day readmission (26.2% vs. 30.2%), and 90-day mortality (3.0% vs. 8.7%) were lower at DCCs compared with non-DCCs (all p < 0.001). In addition, long-term hazards of death among patients undergoing hepatectomy [hazard ratio (HR) 0.64, 95% confidence interval (CI) 0.54-0.75] and pancreatectomy (HR 0.66, 95% CI 0.56-0.78) were lower among patients treated at DCCs (both p < 0.05). While Medicare payments for patients undergoing pancreatic surgery (DCC: $22,200 vs. non-DCC: $22,100; p = 0.772) were comparable among DCC and non-DCC hospitals, Medicare payments for liver resection at DCCs were 13.9% lower than non-DCCs (DCC: $16,700 vs. non-DCC: $19,400; p < 0.001). CONCLUSIONS: Patients undergoing hepatopancreatic surgery at DCCs had better short- and long-term outcomes for the same/lower level of Medicare expenditure as non-DCC hospitals. DCCs provide higher-value surgical care for patients undergoing liver and pancreatic cancer operations.
doi: https://doi.org/10.1245/s10434-019-07677-1
- NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31375766
With the FDA approval of larotrectinib, NTRK fusion assessment has recently become a standard part of management for patients with locally advanced or metastatic cancers. Unlike somatic mutation assessment, the detection of NTRK fusions is not straightforward, and various assays exist at the DNA, RNA, and protein level. Here, we investigate the performance of immunohistochemistry and DNA-based next-generation sequencing to indirectly or directly detect NTRK fusions relative to an RNA-based next-generation sequencing approach in the largest cohort of NTRK fusion positive solid tumors to date. A retrospective analysis of 38,095 samples from 33,997 patients sequenced by a targeted DNA-based next-generation sequencing panel (MSK-IMPACT), 2189 of which were also examined by an RNA-based sequencing assay (MSK-Fusion), identified 87 patients with oncogenic NTRK1-3 fusions. All available institutional NTRK fusion positive cases were assessed by pan-Trk immunohistochemistry along with a cohort of control cases negative for NTRK fusions by next-generation sequencing. DNA-based sequencing showed an overall sensitivity and specificity of 81.1% and 99.9%, respectively, for the detection of NTRK fusions when compared to RNA-based sequencing. False negatives occurred when fusions involved breakpoints not covered by the assay. Immunohistochemistry showed overall sensitivity of 87.9% and specificity of 81.1%, with high sensitivity for NTRK1 (96%) and NTRK2 (100%) fusions and lower sensitivity for NTRK3 fusions (79%). Specificity was 100% for carcinomas of the colon, lung, thyroid, pancreas, and biliary tract. Decreased specificity was seen in breast and salivary gland carcinomas (82% and 52%, respectively), and positive staining was often seen in tumors with neural differentiation. Both sensitivity and specificity were poor in sarcomas. Selection of the appropriate assay for NTRK fusion detection therefore depends on tumor type and genes involved, as well as consideration of other factors such as available material, accessibility of various clinical assays, and whether comprehensive genomic testing is needed concurrently.
doi: https://doi.org/10.1038/s41379-019-0324-7
- Tumour Growth Rate as a validated early radiological biomarker able to reflect treatment-induced changes in Neuroendocrine Tumours; the GREPONET-2 study
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31375514
PURPOSE: TGR represents the percentage change in tumour volume per month (%/m). Previous results from the GREPONET study showed that TGR measured after 3 months (TGR3m) of starting systemic treatment (ST) or watch and wait (WW) was an early biomarker predicting progression-free survival (PFS) in NETs. EXPERIMENTAL DESIGN: Pts from7 centres with advanced grade(G) 1/2 NETs from the pancreas(P)/small bowel(SB) initiating ST/WW were eligible. Computed tomography (CT) / magnetic resonance imaging (MRI) performed at pre-baseline, baseline and 3(+/-1) months of study entry were retrospectively reviewed. Aim-1: explore treatment-induced changes in TGR (ΔTGR3m-BL) (paired T-test) and Aim-2: validate TGR3m (<0.8%/m vs ≥0.8%/m) as an early biomarker in an independent cohort (Kaplan-Meier/Cox Regression). RESULTS: Out of 785 pts screened, 127 were eligible. Mean (SD) TGR0 and TGR3m were 5.4%/m (14.9) and -1.4%/m (11.8), respectively. Mean(SD) ΔTGR3m-BL paired-difference was -6.8%/m(19.3) (p<0.001). Most marked ΔTGR3m-BL (mean (SD);p) were identified with targeted therapies (-11.3%/m(4.7);0.0237) and chemotherapy (-7.9%/m(3.4);0.0261). Multivariable analysis confirmed the absence of previous treatment (Odds Ratio (OR) 4.65 (95%CI 1.31-16.52); p-value0.018) and low TGR3m (continuous variable; OR 1.09 (95%CI 1.01-1.19); p-value0.042) to be independent predictors of radiological objective response. When the multivariable Cox Regression was adjusted to grade (p-value 0.004) and stage (p-value0.017), TGR3m≥0.8 (vs.<0.8) maintained its significance (p<0.001), while TGR0 and ΔTGR3m-BL did not. TGR3m was confirmed as an independent prognosis factor for PFS (external validation; Aim-2) (multivariable HR 2.21 (95%CI 1.21-3.70); p-value0.003). CONCLUSIONS: TGR has a role as biomarker for monitoring response to therapy for early prediction of PFS and radiological objective response.
doi: https://doi.org/10.1158/1078-0432.CCR-19-0963
- Facility Type is Another Factor in the Volume-Outcome Relationship for Complex Hepatopancreatobiliary Procedures
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31372869
doi: https://doi.org/10.1245/s10434-019-07668-2
- Comparative effectiveness of primary tumor resection in patients with stage III pancreatic adenocarcinoma
BMC cancer 2019 Aug;19(1):761
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31370893
BACKGROUND: Previous studies comparing primary tumor resection (PTR) to palliative treatment for advanced-stage pancreatic ductal adenocarcinoma (PDA) were limited by strong selection bias. We used multiple methods to control for confounding and selection bias to estimate the effect of PTR on survival for late-stage PDA. METHODS: Surveillance, Epidemiology, and End Results (SEER) 18 registry database for 2004 through 2014 was retrieved for the present study. A total of 4322 patients with stage III (AJCC, 6th) PDA were included in this study. Propensity score matching (PSM) was performed to eliminate possible bias. In addition, instrumental variable (IV) analysis was utilized to adjust for both measured and unmeasured confounders. RESULTS: A total of 4322 patients with stage III PDA including 552 (12.8%) who underwent PTR, 3770 (87.2%) without PTR, were identified. In the multivariable cohort, a clear prognostic advantage of PTR was observed in overall survival (OS) (P < 0.001) and disease-specific survival (DSS) (P < 0.001) compared to patients after non-surgery therapy. In the PSM cohort, patients in PTR group showed a better OS and DSS (both P values < 0.001) compared to patients in non-surgery group. The survival benefit of PTR for stage III PDA was not observed in the two-stage residual inclusion (2SRI) model. Estimates based on this instrument indicated that patients treated with PTR had similar OS (P = 0.448) and DSS (P = 0.719). In IV analyses stratified by chemotherapy and tumor location, patients undergoing PTR had similar OS and DSS compared to patients in non-surgery group across all subgroups. CONCLUSIONS: Survival with PTR did not differ significantly from palliative treatment in marginal patients with stage III pancreatic adenocarcinoma. High-quality randomized trials are needed to validate these results.
doi: https://doi.org/10.1186/s12885-019-5966-9
- Reply to Comment on Zeng et al, Spatial Distribution of Pancreatic Stones in Chronic Pancreatitis
Pancreas 2019 Aug;48(7):e59
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31306309
doi: https://doi.org/10.1097/MPA.0000000000001351
- Mathematical Model and Study Design Could Be Optimized in Spatial Distribution Analysis of Pancreatic Stones
Pancreas 2019 Aug;48(7):e58
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31306308
doi: https://doi.org/10.1097/MPA.0000000000001362
- Reply to: The Relationship of Acute Pancreatitis and Pancreatic Cancer
Pancreas 2019 Aug;48(7):e57-e58
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31306307
doi: https://doi.org/10.1097/MPA.0000000000001358
- The Relationship of Acute Pancreatitis and Pancreatic Cancer
Pancreas 2019 Aug;48(7):e57
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31306306
doi: https://doi.org/10.1097/MPA.0000000000001357
- Surgical and Oncological Outcomes of Laparoscopic Versus Open Pancreaticoduodenectomy in Patients With Pancreatic Duct Adenocarcinoma
Pancreas 2019 Aug;48(7):861-867
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31306305
It is not clear which of the 2 principal treatments for patients with pancreatic duct adenocarcinoma (PDAC), laparoscopic pancreaticoduodenectomy (LPD) and open pancreaticoduodenectomy (OPD), has greater safety and efficacy. We performed the present meta-analysis to assess the efficacy of both treatments for PDAC patients undergoing LPD. Multiple electronic databases were systematically searched to identify studies (up to October 2018) comparing LPD with OPD for PDAC. Short- and long-term oncological outcomes were evaluated. Six studies were qualified for inclusion criteria in this meta-analysis with a total of 9144 PDAC participants. Regarding safety, there were fewer overall postoperative complications associated with LPD (P = 0.005), but the results were similar in terms of pancreatic fistula and mortality. Laparoscopic pancreaticoduodenectomy was associated with a better trend of performance both in R0 resection (relative risk, 1.03; 95% confidence interval [CI], 1.00-1.07; P = 0.07) and preserved lymph nodes (median, 2.14; 95% CI, -0.21 to 4.49; P = 0.07). Long-term overall survival was comparable between LPD and OPD (hazard ratio, 1.03; 95% CI, 0.95-1.13; P = 0.49). In conclusion, LPD was found to be a suitable alternative to OPD in selected PDAC patients with respect to both surgical and oncological outcomes.
doi: https://doi.org/10.1097/MPA.0000000000001363
- Excess body weight at age <50 years is linked to pancreatic cancer mortality
Cancer 2019 Aug;125(15):2527
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31298753
doi: https://doi.org/10.1002/cncr.32394
- Trends in biomarker discoveries for the early detection and risk stratification of pancreatic cancer using omics studies
Expert review of molecular diagnostics 2019 Aug;19(8):651-654
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31298060
doi: https://doi.org/10.1080/14737159.2019.1643718
- Impact of Changes in the American Joint Committee on Cancer Staging Manual, Eighth Edition, for Pancreatic Ductal Adenocarcinoma
Pancreas 2019 Aug;48(7):876-882
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268985
OBJECTIVE: Consistent and reliable tumor staging is a critical factor in determining treatment strategy, selection of patients for adjuvant therapy, and for therapeutic clinical trials. The aim of this study was to evaluate the number and extent of pancreatic ductal adenocarcinoma (PDAC) cases that would have a different pT, pN, and overall stages based on the new eighth edition American Joint Committee on Cancer staging system when compared with the seventh edition. METHODS: Patients diagnosed with PDAC who underwent pancreaticoduodenectomy, total pancreatectomy, or distal pancreatectomy from 2007 to 2017 were retrospectively reviewed. A total of 340 cases were included. RESULTS: According to the seventh edition, the vast majority of tumors in our cohort were staged as pT3 tumors (88.2%). Restaging these cases with the new size-based pT system resulted in a more equal distribution among the 3 pT categories, with higher percentage of pT2 cases (55%). CONCLUSIONS: The newly adopted pT stage protocol for PDAC is clinically relevant, ensures a more equal distribution among different stages, and allows for a significant prognostic stratification. In contrast, the new pN classification (pN1 and pN2) based on the number of positive lymph nodes failed to show survival differences and remains controversial.
doi: https://doi.org/10.1097/MPA.0000000000001349
- The Surveillance Patterns of Incidentally Detected Pancreatic Cysts Vary Widely and Infrequently Adhere to Guidelines
Pancreas 2019 Aug;48(7):883-887
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268984
OBJECTIVES: We aimed to determine incidental pancreatic cyst (“cyst”) surveillance patterns, predictors of receiving surveillance, and guideline adherence. METHODS: We performed a retrospective cohort study of all patients receiving longitudinal care at a single tertiary care center with a newly diagnosed incidental pancreatic cyst over a 2-year period (2010-2011). All follow-up care was abstracted over a 5-year period. RESULTS: Of 3241 eligible imaging studies reviewed, 100 patients with newly diagnosed incidental cysts eligible for surveillance were identified. A majority (53%) received no follow-up. We identified 4 predictors of cyst surveillance: radiology report conclusion mentioning the cyst (odds ratio [OR], 14.9; 95% confidence interval [CI], 1.9-119) and recommending follow-up (OR, 5.5; 95% CI, 2.1-13.9), pancreas main duct dilation (OR, 10.7; 95% CI, 1.3-89), and absence of multiple cysts (OR, 2.5; 95% CI, 1.1-10.0). Of the 47 patients who received surveillance, 66% met minimum surveillance imaging intervals of at least one guideline. Conversely, 21% of patients met the criteria for overutilization in at least one guideline. CONCLUSIONS: Although guidelines recommend that surgically fit patients with incidental cysts undergo surveillance, most patients receive no follow-up. When follow-up occurs, surveillance patterns vary widely and infrequently conform to guidelines. Interventions to reduce care variation require study.
doi: https://doi.org/10.1097/MPA.0000000000001352
- Alternate Week Gemcitabine and Capecitabine: An Effective Treatment for Patients With Pancreatic Adenocarcinoma
Pancreas 2019 Aug;48(7):927-930
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268983
OBJECTIVE: Determine whether a regimen of fixed dose rate gemcitabine plus capecitabine is effective and tolerable for advanced pancreatic adenocarcinoma. METHODS: We performed a retrospective analysis of 62 patients with locally advanced or metastatic pancreatic adenocarcinoma treated at the University of California San Francisco between 2008 and 2016. Treatment was an alternate week schedule of fixed dose rate 1000 mg/m gemcitabine and capecitabine 1000 mg/m (58 patients), 1200 mg/m (12 patients), or 650 mg/m (1 patient) for intended 12 cycles. We evaluated overall survival (OS), progression-free survival (PFS), radiologic response, and adverse events necessitating treatment modification. RESULTS: For metastatic patients, median OS was 10.3 months (95% confidence interval [CI], 6.7-12.1 months), and PFS was 5.6 months (95% CI, 2.6-7.7 months). In locally advanced patients, OS was 12.0 months (95% CI, 4.9-17.1 months), and PFS was 5.4 months (95% CI, 2.5-9.4 months). Radiologic response for metastatic disease (42 patients) was 19% objective response, 45% stable disease, and 36% progressive disease. Treatment required modification for 22 patients due to adverse events, most frequently hand-foot syndrome (18 patients). CONCLUSIONS: Alternate week schedule of fixed dose rate gemcitabine and capecitabine was active and tolerable for advanced pancreatic adenocarcinoma. Overall survival and PFS were comparable to first-line treatments. Importantly, adverse effects appear less severe than first-line treatments.
doi: https://doi.org/10.1097/MPA.0000000000001354
- Induction Therapy in Localized Pancreatic Cancer
Pancreas 2019 Aug;48(7):913-919
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268982
OBJECTIVES: Pancreatic cancer (PDAC) with localized stage includes resectable (RPC), borderline resectable (BRPC), or locally advanced unresectable (LAPC). Standard of care for RPC is adjuvant chemotherapy. There are no prospective randomized trials for best treatment of BRPC and LAPC. We evaluate the impact of induction chemotherapy on localized PDAC. METHODS: Charts of PDAC patients treated at Emory University between 2009 and 2016 were reviewed. The primary end point was overall survival (OS). RESULTS: A total of 409 localized PDACs were identified. Resectability was prospectively determined at a multidisciplinary tumor conference. Median age was 67 years (range, 30-92 years), 49% were male, 66% were white, 171 had RPC, 131 had BRPC, and 107 had LAPC. Median OSs for RPC, BRPC, and LAPC were 19.5, 16.1, and 12.7 months, respectively. Type of chemotherapy and age were predictors of OS. Induction chemotherapy was used in 106 with BRPC (81%) and 74 with RPC (56.5%); patients with BRPC who received combination chemotherapy and resection had a median OS of 31.5 compared with 19.5 months in patients with RPC (P = 0.0049). Patients with LAPC had a median OS of 12.7 months. CONCLUSIONS: In patients with BRPC who undergo resection after induction treatment, the OS was significantly better than in patients with RPC. Neoadjuvant treatment should be considered for all localized PDACs.
doi: https://doi.org/10.1097/MPA.0000000000001353
- Acute Recurrent and Chronic Pancreatitis as Initial Manifestations of Cystic Fibrosis and Cystic Fibrosis Transmembrane Conductance Regulator-Related Disorders
Pancreas 2019 Aug;48(7):888-893
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268981
OBJECTIVES: Recurrent pancreatitis is considered a rare manifestation of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction; this case series highlights that pancreatitis can be a presenting symptoms of cystic fibrosis (CF) or a CFTR-related disorder (CFTR-RD). METHODS: Retrospective review of patients younger than 30 years diagnosed as having acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP) and subsequently diagnosed as having CF or CFTR-RD. RESULTS: Among 18 patients, median time from diagnosis of ARP/CP to diagnosis of CF was 0.4 years (range, 0-33 years). Eight were classified as having CF by elevated sweat chloride testing (SCT). Five had intermediate SCT (30-59 mmol/L) with 2 pathogenic mutations. Five had CFTR-RD with intermediate SCT and 0 to 1 pathogenic mutations. Eight patients (44%) had exocrine pancreatic insufficiency, and pancreatic fluid collections were more common in this group. Based on the CFTR mutation, 6 patients were eligible for CFTR potentiator therapy, although none received it during the study period. Nine of the 18 had ≥1 other likely CF manifestations, including sinusitis (33%), nasal polyps (11%), pneumonia (22%), and gallbladder disease (22%). CONCLUSIONS: Cystic fibrosis or CFTR-RD can present as ARP/CP. Complete diagnostic testing for CFTR-RD in patients with ARP/CP will broaden treatment options and help to identify comorbid illness.
doi: https://doi.org/10.1097/MPA.0000000000001350
- Significance of Lymph Node Metastasis in Resectable Well-differentiated Pancreatic Neuroendocrine Tumor
Pancreas 2019 Aug;48(7):943-947
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268980
OBJECTIVES: Understanding the effect of lymph node metastasis (LNM) on prognosis in pancreatic neuroendocrine neoplasm is helpful for surgery and follow-up. In this study, we investigated the significance of LNM in well-differentiated pancreatic neuroendocrine tumors (PanNETs) according to the World Health Organization 2017 classification. METHODS: We retrospectively collected data for 95 consecutive patients with PanNET who underwent pancreatic resection with curative intent between January 2008 and December 2017 at 6 institutions. The clinicopathological factors were compared in patients with and without LNM, and prognostic factors were analyzed. RESULTS: Lymph node metastasis was significantly associated with malignant potential of PanNET, such as larger tumor size, higher Ki-67 index, higher tumor grade, and higher incidence of lymphatic, vessel, and neural invasion. Lymph node metastasis was also associated with disease-free but not overall survival. Multivariate analysis identified NET grade 2 (G2) and G3 as independent risk factors for recurrence after curative resection. CONCLUSIONS: World Health Organization 2017 classification was the most independent prognostic factor in patients with resectable well-differentiated PanNETs. Patients with G2 and higher-grade tumors require lymph node dissection to improve prognosis.
doi: https://doi.org/10.1097/MPA.0000000000001355
- Gastric Emptying and Distal Gastrectomy Independently Enhance Postprandial Glucagon-Like Peptide-1 Release After a Mixed Meal and Improve Glycemic Control in Subjects Having Undergone Pancreaticoduodenectomy
Pancreas 2019 Aug;48(7):953-957
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268979
OBJECTIVES: New-onset diabetes frequently resolves after pancreaticoduodenectomy (PD). Glucagon-like peptide-1 (GLP-1) conceivably is involved as its release is enhanced by rapid gastric emptying and distal bowel exposure to nutrients. We aimed at studying factors associated with GLP-1 release after PD. METHODS: Fifteen PD subjects with distal gastrectomy (Whipple) and 15 with pylorus preservation were evaluated. A test meal containing 1 g paracetamol to measure gastric emptying was ingested. Blood for the measurement of paracetamol, glucose, insulin, and GLP-1 was drawn at baseline and 10, 20, 30, 60, 90, 120, 150, and 180 minutes thereafter. The Matsuda index of insulin sensitivity was calculated. RESULTS: In univariate analysis, gastric emptying correlated with GLP-1. Glucagon-like peptide-1 responses to the modes of operation did not differ. Multiple regression analysis confirmed gastric emptying and Whipple versus pylorus-preserving pancreaticoduodenectomy as independent predictors of GLP-1 release. The Matsuda index of insulin sensitivity correlated with GLP-1 concentrations and inversely with body mass index. Patients after Whipple procedure revealed lower glycated hemoglobin as compared with pylorus-preserving pancreaticoduodenectomy. CONCLUSIONS: Following PD, the postprandial GLP-1 release seems to be enhanced by rapid gastric emptying and to improve insulin sensitivity. Partial gastrectomy versus pylorus preservation enhanced the release of GLP-1, conceivably because of greater distal bowel exposure to undigested nutrients.
doi: https://doi.org/10.1097/MPA.0000000000001361
- Endogenous Gastrin Collaborates With Mutant KRAS in Pancreatic Carcinogenesis
Pancreas 2019 Aug;48(7):894-903
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268978
OBJECTIVE: The KRAS gene is the most frequently mutated gene in pancreatic cancer, and no successful anti-Ras therapy has been developed. Gastrin has been shown to stimulate pancreatic cancer in an autocrine fashion. We hypothesized that reactivation of the peptide gastrin collaborates with KRAS during pancreatic carcinogenesis. METHODS: LSL-Kras; P48-Cre (KC) mutant KRAS transgenic mice were crossed with gastrin-KO (GKO) mice to develop GKO/KC mice. Pancreata were examined for 8 months for stage of pancreatic intraepithelial neoplasia lesions, inflammation, fibrosis, gastrin peptide, and microRNA expression. Pancreatic intraepithelial neoplasias from mice were collected by laser capture microdissection and subjected to reverse-phase protein microarray, for gastrin and protein kinases associated with signal transduction. Gastrin mRNA was measured by RNAseq in human pancreatic cancer tissues and compared to that in normal pancreas. RESULTS: In the absence of gastrin, PanIN progression, inflammation, and fibrosis were significantly decreased and signal transduction was reversed to the canonical pathway with decreased KRAS. Gastrin re-expression in the PanINs was mediated by miR-27a. Gastrin mRNA expression was significantly increased in human pancreatic cancer samples compared to normal human pancreas controls. CONCLUSIONS: This study supports the mitogenic role of gastrin in activation of KRAS during pancreatic carcinogenesis.
doi: https://doi.org/10.1097/MPA.0000000000001360
- New-Onset Diabetes Mellitus After Chronic Pancreatitis Diagnosis: A Systematic Review and Meta-analysis
Pancreas 2019 Aug;48(7):868-875
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268977
OBJECTIVES: The aim of this study was to assess the occurrence of new-onset diabetes mellitus (DM) after chronic pancreatitis (CP) diagnosis via systematic review and meta-analysis. METHODS: A systematic review of literature and meta-analysis of relevant reports were performed. The primary outcome measures studied were newly diagnosed DM and DM treated with insulin. For the binary outcomes, pooled prevalence and 95% confidence interval (CI) were calculated. METHODS: Fifteen studies involving 8970 patients were eligible. The incidence of new-onset DM after CP diagnosis was 30% (95% CI, 27%-33%). Among all patients, 17% (95% CI, 13%-22%) developed insulin-dependent new-onset DM. The prevalence of newly diagnosed DM after CP diagnosis increased from 15% within 36 months to 33% after 60 months. The proportion of alcoholic CP, sex, age, and body mass index had minimal effect on the studied outcomes. CONCLUSIONS: This systematic review identified a clinically relevant risk of new-onset DM after CP diagnosis. Therefore, patients should be informed of the risk of DM and monitored.
doi: https://doi.org/10.1097/MPA.0000000000001359
- The Importance of a Conjoint Analysis of Tumor-Associated Macrophages and Immune Checkpoints in Pancreatic Cancer
Pancreas 2019 Aug;48(7):904-912
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268976
OBJECTIVES: Tumor-associated macrophages are dominant players in establishing the inmmunosuppressive microenvironment in pancreatic ductal adenocarcinoma (PDAC). Immune checkpoint inhibitor monotherapy has achieved limited clinical effectiveness. To date, the interaction of macrophages and checkpoint regulators and their correlation with clinicopathologic characteristics in PDAC have been largely unavailable. METHODS: Macrophages and immune checkpoint expression were assessed by immunohistochemistry from 80 PDAC samples. Clinicopathologic features and the prognostic value of each marker were evaluated. In vitro changes in the expression of immune markers in cocultured macrophages and PDAC cells were detected by Western blot and immunosorbance assays. RESULTS: The macrophages marker CD163 and the checkpoint marker programmed death-ligand 1 (PD-L1) remained as the independent prognostic factors for overall survival (hazard ratio, 2.543; P = 0.017 and hazard ratio, 2.389; P = 0.021). Furthermore, integrated analysis of CD163 and PD-L1 served as more optimal indicators of survival (P = 0.000). In vitro coculture of macrophages and PDAC cells significantly increased the expression of CD163 and PD-L1, compared with monocultured counterpart (P < 0.05). CONCLUSIONS: Combined analysis of CD163 and PD-L1 was enhanced indicators of survival in PDAC patients. The interaction of macrophages and immune checkpoints implied the value of the combination therapy.
doi: https://doi.org/10.1097/MPA.0000000000001364
- Correlation of DOTATOC Uptake and Pathologic Grade in Neuroendocrine Tumors
Pancreas 2019 Aug;48(7):948-952
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268975
OBJECTIVES: Gallium (Ga)-DOTATOC is a somatostatin analog used to detect neuroendocrine tumors (NETs). Ki-67 proliferation index (Ki-67 PI) has been established as a prognostic factor in NETs. We aimed to evaluate whether a correlation exists between Ki-67 PI and somatostatin receptor positron emission tomography (SSTR-PET) uptake. METHODS: We retrospectively reviewed 238 DOTATOC PET scans between 2014 and 2016. Patients were excluded if DOTATOC PET was performed more than 365 days from the date of biopsy. Maximum standardized uptake values (SUVmax) of SSTR-PET from biopsied lesions were measured and correlated with Ki-67 PI using the Pearson correlation coefficient. RESULTS: Among 110 lesions from 90 patients, DOTATOC PET had 92.7% sensitivity and 100% specificity (102 true positives, 8 false negatives) for detection of NETs. Among 63 lesions from 54 patients with Ki-67 PI available, there were 27 grade 1 lesions [median Ki-67 PI, 1.0%; interquartile range (IQR), 1.0-2.0], 30 grade 2 lesions (median, Ki-67 PI 7.5%; IQR, 5-10), and 6 grade 3 lesions (median Ki-67 PI, 30%; IQR, 26-34). There was a correlation between Ki-67 PI and SUVmax (r = -0.3, P = 0.018). CONCLUSIONS: Our analysis demonstrates an inverse correlation between Ki-67 PI and SUVmax in NETs. Somatostatin receptor-PET provides additional information that can help guide management of NETs.
doi: https://doi.org/10.1097/MPA.0000000000001356
- Diagnostic and Management Challenges in Vasoactive Intestinal Peptide Secreting Tumors: A Series of 15 Patients
Pancreas 2019 Aug;48(7):934-942
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268974
OBJECTIVES: Vasoactive intestinal peptide-secreting tumors (VIPomas) are rare functioning neuroendocrine tumors often characterized by a difficult-to-control secretory syndrome and high potential to develop metastases. We hereby present the characteristics of 15 cases of VIPomas and provide a recent literature review. METHODS: This was a retrospective data analysis of 15 patients with VIPoma from 3 different centers and literature research through PubMed database during the last 10 years. RESULTS: Fifteen patients with VIPomas (9 with hepatic metastases at diagnosis) with watery diarrhea and raised VIP levels were studied. Ten patients (67%) had grade 2 tumors, 6 of 15 had localized disease and underwent potentially curative surgery, whereas the remaining 9 received multiple systemic therapies; 3 patients died during follow-up. The median overall survival was 71 months (range, 41-154 months). Patients who were treated with curative surgery (n = 7) had longer median overall survival compared with patients who were treated with other therapeutic modalities (44 vs 33 months). CONCLUSIONS: The management of VIPomas is challenging requiring the application of multiple treatment modalities. Patients who underwent surgical treatment with curative intent appear to have higher survival rate. Central registration and larger prospective studies are required to evaluate the effect of currently employed therapies in these patients.
doi: https://doi.org/10.1097/MPA.0000000000001347
- Complications to Chronic Pancreatitis and Etiological Risk Factors: A Continental Divide?
The American journal of gastroenterology 2019 Aug;114(8):1353
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31211705
doi: https://doi.org/10.14309/ajg.0000000000000302
- Benchmark, Textbook or Optimal Pancreatic Surgery?
Annals of surgery 2019 Aug;270(2):219-220
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31188222
doi: https://doi.org/10.1097/SLA.0000000000003377
- Comparisons of Outcomes of Real-World Patients With Advanced Pancreatic Cancer Treated With FOLFIRINOX Versus Gemcitabine and Nab-Paclitaxel: A Population-Based Cohort Study
Pancreas 2019 Aug;48(7):920-926
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31180981
OBJECTIVES: The aim of this study was to compare the efficacy and safety of FOLFIRINOX (5-FU/leucovorin, irinotecan, and oxaliplatin) and gemcitabine/nab-paclitaxel (GnP) in patients with advanced pancreatic cancer. METHODS: Patients with newly diagnosed advanced pancreatic cancer in Saskatchewan, Canada, from 2011 to 2016, who received FOLFIRINOX or GnP were assessed. A Cox proportional multivariate analysis was performed to evaluate prognostic variables. RESULTS: One hundred nineteen eligible patients with median age of 61 years and male/female ratio of 70:49 were identified. Seventy-seven percent had metastatic disease. Of 119 patients, 86 (72%) received FOLFIRINOX and 33 (28%) were treated with GnP. Median progression-free survival of the FOLFIRINOX group was 6.0 months [95% confidence interval (CI), 4.5-7.5] versus 4.0 months (95% CI, 2.9-5.1) with GnP (P = 0.39). The median overall survival of the FOLFIRINOX group was 9.0 months (95% CI, 7-11) compared with 9.0 months (95% CI, 4.2-13.8) with GnP (P = 0.88). On multivariate analysis, albumin [hazard ratio (HR), 0.63; 95% CI, 0.41-0.97], male sex (HR, 0.65; 95% CI, 0.43-0.97), and second-line therapy (HR, 0.50; 95% CI, 0.28-0.86) were correlated with survival. CONCLUSIONS: Our results showed that real-world patients with advanced pancreatic cancer treated with FOLFIIRNOX or GnP had comparable survival with different safety profile.
doi: https://doi.org/10.1097/MPA.0000000000001340
- Differences in Pancreatic Cancer Incidence Rates and Temporal Trends Across Asian Subpopulations in California (1988-2015)
Pancreas 2019 Aug;48(7):931-933
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31180980
OBJECTIVE: Ethnic disparities in pancreatic cancer (PanCan) incidence exist, but little is known about incidence trends in heterogeneous Asian Americans. We examined PanCan incidence and temporal patterns among detailed ethnic populations, including Asian American subgroups. METHODS: A total of 71,099 invasive exocrine PanCan cases were identified using the California Cancer Registry between 1988 and 2015. Cases were grouped into mutually exclusive groups of non-Hispanic (NH) white, NH black, Hispanic, NH Asian/Pacific Islander (API), and NH American Indian/Alaska Native (AIAN). Asians were further identified by specific ethnicity. RESULTS: The age-adjusted incidence rates (AAIRs, per 100,000) of PanCan varied significantly across racial/ethnic groups, ranging from the highest of 10.4 in NH blacks to 7.6 in NH whites, 7.1 in Hispanics, 6.2 in NH APIs, and to the lowest of 5.2 in NH AIAN. Despite the relatively low rate in the NH APIs, the rates across Asian subgroups varied significantly, with rates similar to NH whites in Japanese (8.1) and Koreans (7.5) to the low rate in South Asians (4.4). CONCLUSIONS: Significant heterogeneity of PanCan incidence in disaggregated Asian Americans is a novel finding. These results fill a gap regarding PanCan burden in Asian Americans and underscore the importance of disaggregating ethnic populations in cancer research.
doi: https://doi.org/10.1097/MPA.0000000000001337
- Oncogenic NRG1 Fusions: A New Hope for Targeted Therapy in Pancreatic Cancer
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Aug;25(15):4589-4591
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31164372
Approximately 8%-10% of pancreatic ductal adenocarcinoma cases are KRAS wild type. In a subset of these tumors, NRG1 gene fusions have been identified as targetable oncogenic drivers, a discovery that highlights the importance of deep molecular characterization for KRAS wild-type pancreatic cancers and provides a novel treatment strategy in this disease.See related article by Jones et al., p. 4674.
doi: https://doi.org/10.1158/1078-0432.CCR-19-1280
- Proton Radiotherapy for Isolated Local Recurrence of Primary Resected Pancreatic Ductal Adenocarcinoma
Annals of surgical oncology 2019 Aug;26(8):2587-2594
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31147994
BACKGROUND: The optimal treatment for isolated local recurrence (ILR) of pancreatic adenocarcinoma (PDAC) after surgical resection remains unclear. This study aimed to evaluate the safety and efficacy of proton radiotherapy (PRT) for ILR of PDAC after surgery. METHODS: The medical records of patients with ILR of PDAC after surgery who underwent proton beam therapy between 2011 and 2015 at Hyogo Ion Beam Medical Center were retrospectively studied. RESULTS: The study analyzed 30 patients (14 women and 16 men) with a median age of 65 years (range 38-81 years) who had initially undergone pancreatoduodenectomy (n = 23) or distal pancreatectomy (n = 7) for their primary tumors. Upon ILR, PRT was administered with a median total cumulative dose of 67.5 gray equivalent (GyE) (range 50-67.5 GyE) using 19 to 25 fractions. For 25 patients, concurrent chemotherapy was administered using gemcitabine (n = 18) or S-1 (n = 7). Four patients (13.3%) experienced acute grade ≥ 3 gastrointestinal toxicities. After a median follow-up period of 17.6 months (range 2.1-50.4 months), 23 patients had experienced tumor progression and 10 had died. Nine patients (30%) experienced local tumor progression. The median overall, progression-free, and local progression-free survival rates were 26.1, 12.3, and 41.2 months, respectively. Pre-PRT serum levels of cancer antigen 19-9 higher than 100 U/mL and duke pancreatic monoclonal antigen type 2 higher than 150 U/mL were significantly associated with shorter progression-free survival rates. CONCLUSIONS: Proton radiotherapy for ILR of PDAC after surgery is well tolerated and produces good locoregional control and should be considered for eligible patients.
doi: https://doi.org/10.1245/s10434-019-07471-z
- Controversies on the endoscopic and surgical management of pain in patients with chronic pancreatitis: pros and cons!
Gut 2019 08;68(8):1343-1351
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31129569
doi: https://doi.org/10.1136/gutjnl-2019-318742
- Stromal hyaluronan accumulation is associated with low tumor grade and nodal metastases in pancreatic ductal adenocarcinoma
Human pathology 2019 Aug;90():37-44
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31121193
Pancreatic ductal adenocarcinoma is an aggressive malignancy characterized by abundant desmoplastic stroma. Hyaluronan is a prominent stromal component of pancreatic ductal adenocarcinoma and is associated with unique clinical-pathological profiles in other tumor types. The current study aimed to delineate clinical and pathological features associated with hyaluronan accumulation in pancreatic ductal adenocarcinoma using a novel hyaluronan-binding assay currently being used in a clinical trial targeting hyaluronan. Sixty-four formalin-fixed, paraffin-embedded samples of pancreatic ductal adenocarcinomas from 49 patients treated at a single tertiary care hospital were stained. Fifty-two percent of tumors had high levels of hyaluronan. High levels were associated with low tumor grade and lymph node metastases, novel associations not previously seen in pancreatic ductal adenocarcinoma. This study has elucidated a novel clinical-pathological profile in pancreatic ductal adenocarcinomas using a new assay, suggesting hyaluronan may act as a biomarker for a subset of pancreatic tumors that could be targeted by hyaluronan-degrading agents.
doi: https://doi.org/10.1016/j.humpath.2019.05.004
- RAS Mutation Decreases Overall Survival After Optimal Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy of Colorectal Peritoneal Metastasis: A Modification Proposal of the Peritoneal Surface Disease Severity Score
Annals of surgical oncology 2019 Aug;26(8):2595-2604
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31111351
BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are currently the most accepted treatment for peritoneal metastases from colorectal cancer. Restrictive selection criteria are essential to obtain the best survival benefits for this complex procedure. The most widespread score for patient selection, the peritoneal surface disease severity score (PSDSS), does not include current biological factors that are known to influence on prognosis. We investigated the impact of including RAS mutational status in the selection criteria for these patients. METHODS: We studied the risk factors for survival by multivariate analysis using a prospective database of consecutive patients with carcinomatosis from colorectal origin treated by CRS and HIPEC in our unit from 2009 to 2017. The risk factors obtained were validated in a multicentre, international cohort, including a total of 520 patients from 15 different reference units. RESULTS: A total of 77 patients were selected for local análisis. Only RAS mutational status (HR: 2.024; p = 0.045) and PSDSS stage (HR: 2.90; p = 0.009) were shown to be independent factors for overall survival. Early PSDSS stages I and II associated to RAS mutations impaired their overall survival with no significant differences with PSDSS stage III overall survival (p > 0.05). These results were supported by the international multicentre validation. CONCLUSIONS: By including RAS mutational status, we propose an updated RAS-PSDSS score that outperforms PSDSS alone providing a quick and feasible preoperative assessment of the expected overall survival for patients with carcinomatosis from colorectal origin undergone to CRS + HIPEC.
doi: https://doi.org/10.1245/s10434-019-07378-9
- Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: a non-randomised, multicentre, open-label, phase 1 study
The lancet. Gastroenterology & hepatology 2019 Aug;4(8):611-621
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31109808
BACKGROUND: This study aimed to assess the safety and tolerability of the immune checkpoint inhibitor nivolumab, as monotherapy or combined with chemotherapy, in Japanese patients with biliary tract cancer. METHODS: This multicentre, open-label, phase 1 trial was done at four cancer centres in Japan. Eligible patients were aged 20-79 years, had biliary tract adenocarcinoma (intrahepatic bile duct cancer, extrahepatic bile duct cancer, gallbladder cancer, or ampullary cancer), Eastern Cooperative Oncology Group performance status 0 or 1, adequate hepatic, renal, and haematological function, and tumour tissue samples for PD-L1 expression analysis. Patients with unresectable or recurrent biliary tract cancer that was refractory or intolerant to gemcitabine-based treatment regimens received nivolumab monotherapy (240 mg every 2 weeks [monotherapy cohort]). Chemotherapy-naive patients with unresectable or recurrent biliary tract cancer received nivolumab (240 mg every 2 weeks) and cisplatin (25 mg/m2) plus gemcitabine (1000 mg/m2) chemotherapy (combined therapy cohort). The primary objective was to assess tolerability and safety. The primary objective was assessed in the safety population of all patients who had received at least one dose of nivolumab. This study is registered with www.clinicaltrials.jp, number JapicCTI-153098, and follow-up is ongoing. FINDINGS: 30 patients were enrolled into each cohort between Jan 13, 2016, and April 19, 2017. Data cutoff was Aug 31, 2017. In the monotherapy cohort, the most frequently reported treatment-related adverse events were decreased appetite (five [17%]), malaise (four [13%]), and pruritus (four [13%]). Grade 3-4 treatment-related adverse events were reported by three (10%) patients (rash, maculopapular rash, and amylase increase) and treatment-related serious adverse events were reported by one (3%) patient (pleurisy). In the combined therapy cohort, the most frequently reported treatment-related adverse events were neutrophil count decrease (any grade 25 [83%]; grade 3-4 in 23 [77%] patients) and platelet count decrease (any grade 25 [83%] of 30; grade 3-4 in 15 [50%] patients). Six (20%) patients reported 11 treatment-related serious adverse events (platelet count decrease [three patients], febrile neutropenia [two patients], neutrophil count decrease, anaemia, anaphylactic reaction, decreased appetite, pyrexia, and myocarditis [one patient each]). In the monotherapy cohort, median overall survival was 5·2 months (90% CI 4·5-8·7), median progression-free survival was 1·4 months (90% CI 1·4-1·4), and one of 30 patients had an objective response. In the combined therapy cohort, median overall survival was 15·4 months (90% CI 11·8-not estimable), median progression-free survival was 4·2 months (90% CI 2·8-5·6), and 11 of 30 patients had an objective response. INTERPRETATION: Nivolumab had a manageable safety profile and signs of clinical activity in patients with unresectable or recurrent biliary tract cancer. This initial assessment of nivolumab for the treatment of advanced biliary tract cancer provides supportive evidence for future larger randomised studies of nivolumab in this difficult to treat cancer. FUNDING: Ono Pharmaceutical Co Ltd and Bristol-Myers Squibb Inc.
doi: https://doi.org/10.1016/S2468-1253(19)30086-X
- NRG1 Gene Fusions Are Recurrent, Clinically Actionable Gene Rearrangements in KRAS Wild-Type Pancreatic Ductal Adenocarcinoma
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Aug;25(15):4674-4681
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31068372
PURPOSE: Gene fusions involving neuregulin 1 (NRG1) have been noted in multiple cancer types and have potential therapeutic implications. Although varying results have been reported in other cancer types, the efficacy of the HER-family kinase inhibitor afatinib in the treatment of NRG1 fusion-positive pancreatic ductal adenocarcinoma is not fully understood. EXPERIMENTAL DESIGN: Forty-seven patients with pancreatic ductal adenocarcinoma received comprehensive whole-genome and transcriptome sequencing and analysis. Two patients with gene fusions involving NRG1 received afatinib treatment, with response measured by pretreatment and posttreatment PET/CT imaging. RESULTS: Three of 47 (6%) patients with advanced pancreatic ductal adenocarcinoma were identified as KRAS wild type by whole-genome sequencing. All KRAS wild-type tumors were positive for gene fusions involving the ERBB3 ligand NRG1. Two of 3 patients with NRG1 fusion-positive tumors were treated with afatinib and demonstrated a significant and rapid response while on therapy. CONCLUSIONS: This work adds to a growing body of evidence that NRG1 gene fusions are recurrent, therapeutically actionable genomic events in pancreatic cancers. Based on the clinical outcomes described here, patients with KRAS wild-type tumors harboring NRG1 gene fusions may benefit from treatment with afatinib.See related commentary by Aguirre, p. 4589.
doi: https://doi.org/10.1158/1078-0432.CCR-19-0191
- Contemporary Improvements in Postoperative Mortality After Major Cancer Surgery are Associated with Weakening of the Volume-Outcome Association
Annals of surgical oncology 2019 Aug;26(8):2348-2356
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31065959
BACKGROUND: Regionalization of complex visceral surgery across the United States has followed identification of a volume-outcome association. However, improvements in postoperative mortality overall during the last decade may have weakened the strength of this association. METHODS: The National Cancer Database was used to identify patients undergoing colon, esophageal, liver, and pancreatic surgery from 2003 to 2011. Hospitals were divided into low-volume (< 33rd %tile), medium-volume (34-66th %tile), and high-volume (> 67th %tile) groups. Annual cancer-specific adjusted observed versus expected (O/E) ratios for 30- and 90-day mortality for each volume strata were calculated and plotted over time. RESULTS: In the year 2003, the O/E ratios decreased from low- to medium- to high-volume hospitals for all cancer surgeries for both 30- and 90-day mortality, indicating a strong volume-outcome relationship. For all volume strata, the O/E ratios trended downward from 2003 to 2011 for both 30- and 90-day mortality for all cancer surgeries. This trend was more pronounced for low- and medium-volume than for high-volume hospitals. Consequently, by 2011 the confidence intervals of the O/E ratios for the low-volume groups, and particularly for the medium-volume groups, overlapped those for the high-volume groups for most of the cancer surgeries studied. CONCLUSIONS: The volume-outcome association for major cancer surgery is dynamic and has attenuated over time primarily due to improvements in postoperative mortality at low- and medium-volume hospitals.
doi: https://doi.org/10.1245/s10434-019-07413-9
- Mesothelin-Targeted Thorium-227 Conjugate (MSLN-TTC): Preclinical Evaluation of a New Targeted Alpha Therapy for Mesothelin-Positive Cancers
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Aug;25(15):4723-4734
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31064781
PURPOSE: Targeted thorium-227 conjugates (TTC) represent a new class of molecules for targeted alpha therapy (TAT). Covalent attachment of a 3,2-HOPO chelator to an antibody enables specific complexation and delivery of the alpha particle emitter thorium-227 to tumor cells. Because of the high energy and short penetration range, TAT efficiently induces double-strand DNA breaks (DSB) preferentially in the tumor cell with limited damage to the surrounding tissue. We present herein the preclinical evaluation of a mesothelin (MSLN)-targeted thorium-227 conjugate, BAY 2287411. MSLN is a GPI-anchored membrane glycoprotein overexpressed in mesothelioma, ovarian, pancreatic, lung, and breast cancers with limited expression in healthy tissue. EXPERIMENTAL DESIGN: The binding activity and radiostability of BAY 2287411 were confirmed bioanalytically. The mode-of-action and antitumor potency of BAY 2287411 were investigated in vitro and in vivo in cell line and patient-derived xenograft models of breast, colorectal, lung, ovarian, and pancreatic cancer. RESULTS: BAY 2287411 induced DSBs, apoptotic markers, and oxidative stress, leading to reduced cellular viability. Furthermore, upregulation of immunogenic cell death markers was observed. BAY 2287411 was well-tolerated and demonstrated significant antitumor efficacy when administered via single or multiple dosing regimens in vivo. In addition, significant survival benefit was observed in a disseminated lung cancer model. Biodistribution studies showed specific uptake and retention of BAY 2287411 in tumors and enabled the development of a mechanistic pharmacokinetic/pharmacodynamic model to describe the preclinical data. CONCLUSIONS: These promising preclinical results supported the transition of BAY 2287411 into a clinical phase I program in mesothelioma and ovarian cancer patients (NCT03507452).
doi: https://doi.org/10.1158/1078-0432.CCR-18-3476
- GNAS but Not Extended RAS Mutations Spectrum are Associated with a Better Prognosis in Intraductal Pancreatic Mucinous Neoplasms
Annals of surgical oncology 2019 Aug;26(8):2640-2650
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31025231
BACKGROUND: The management of intraductal papillary mucinous neoplasms (IPMNs) is mainly based on imaging features and clinical symptoms, and remains challenging. OBJECTIVE: The aim of this study was to assess GNAS, RAS family (KRAS, NRAS and HRAS), BRAF, and PIK3CA mutation status in resected IPMNs and correlate it with clinicopathological characteristics and patient survival. METHODS: Overall, 149 consecutive unselected patients who underwent pancreatectomy for IPMNs were included. After dissection from formalin-fixed and paraffin-embedded tumors, GNAS mutational screening was assessed by allelic discrimination using Taqman® probes and confirmed by SNaPshot analysis. RAS family, BRAF, and PIK3CA mutational screening was assessed by high resolution melt and Sanger sequencing. RESULTS: Gastric- and intestinal-type IPMNs were the most frequent lesions (52% and 41%, respectively). Intestinal-type IPMNs were more frequently associated high-grade dysplasia (49%) and were the only IPMNs associated with colloid-type carcinoma. All pancreatobiliary IPMNs were invasive lesions, located in the main pancreatic duct. GNAS-activating mutations were strongly associated with the intestinal phenotype (p < 10-4), while RAS pathway mutations were not associated with any particular phenotype. Mutations within other members of the epidermal growth factor receptor (EGFR) pathway were very rare (2%). GNAS-mutated IPMNs were rarely invasive (11%) and almost exclusively (83%) of the colloid type. For invasive lesions, multivariate analyses determined that only node negativity was associated with improved cancer-specific survival, but, in univariate analysis, GNAS mutation was associated with prolonged survival. CONCLUSION: In patients selected for surgery, GNAS mutation analysis and tumor phenotype can help to better predict patient prognosis. In the near future, a more precise mutational analysis of IPMNs might help to better tailor their management.
doi: https://doi.org/10.1245/s10434-019-07389-6
- The Pancreas as a Site of Metastasis or Second Primary in Patients with Small Bowel Neuroendocrine Tumors
Annals of surgical oncology 2019 Aug;26(8):2525-2532
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31011904
BACKGROUND: The small bowel and pancreas are the most common primary sites of neuroendocrine tumors (NETs) giving rise to metastatic disease. Some patients with small bowel NETs (SBNETs) present with synchronous or metachronous pancreatic NETs (PNETs), and it is unclear whether these are separate primaries or metastases from one site to the other. METHODS: A surgical NET database including patients undergoing operations for SBNETs or PNETs was reviewed. Patients with synchronous or metachronous tumors in both the small bowel and pancreas were identified, and available tissues from primary tumors and metastases were examined using a 4-gene quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC) panel developed for evaluating NETs of unknown primary. RESULTS: Of 338 patients undergoing exploration, 11 had NETs in both the small bowel and pancreas. Tissues from 11 small bowel tumors, 9 pancreatic tumors, and 10 metastases were analyzed. qPCR and IHC data revealed that three patients had separate SBNET and PNET primaries, and five patients had SBNETs that metastasized to the pancreas. Pancreatic tissue was unavailable in two patients, and qPCR and IHC gave discrepant results in one patient. CONCLUSIONS: NETs in both the small bowel and pancreas were found in 3% of our patients. In nearly two-thirds of evaluable patients, the pancreatic tumor was a metastasis from the SBNET primary, while in the remaining one-third of patients it represented a separate primary. Determining the origin of these tumors can help guide the choice of systemic therapy and surgical management.
doi: https://doi.org/10.1245/s10434-019-07370-3
- ASO Author Reflections: Tending Towards a Personalized Medicine for Colorectal Carcinomatosis by Adding the RAS Mutation Status in the Workup for CRS and HIPEC
Annals of surgical oncology 2019 Aug;26(8):2605-2606
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31004296
doi: https://doi.org/10.1245/s10434-019-07362-3
- Defining the Role of Lymphadenectomy for Pancreatic Neuroendocrine Tumors: An Eight-Institution Study of 695 Patients from the US Neuroendocrine Tumor Study Group
Annals of surgical oncology 2019 Aug;26(8):2517-2524
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31004295
BACKGROUND: Preoperative factors that reliably predict lymph node (LN) metastases in pancreatic neuroendocrine tumors (PanNETs) are unclear. The number of LNs needed to accurately stage PanNETs has not been defined. METHODS: Patients who underwent curative-intent resection of non-functional PanNETs at eight institutions from 2000 to 2016 were analyzed. Preoperative factors associated with LN metastases were identified. A procedure-specific target for LN retrieval to accurately stage patients was determined. RESULTS: Of 695 patients who underwent resection, 33% of tumors were proximal (head/uncinate) and 67% were distal (neck/body/tail). Twenty-six percent of patients (n = 158) had LN-positive disease, which was associated with a worse 5-year recurrence-free survival (RFS; 60% vs. 86%; p < 0.001). The increasing number of positive LNs was not associated with worse RFS. Preoperative factors associated with positive LNs included tumor size ≥ 2 cm (odds ratio [OR] 6.6; p < 0.001), proximal location (OR 2.5; p < 0.001), moderate versus well-differentiation (OR 2.1; p = 0.006), and Ki-67 ≥ 3% (OR 3.1; p < 0.001). LN metastases were also present in tumors without these risk factors: < 2 cm (9%), distal location (19%), well-differentiated (23%), and Ki-67 < 3% (16%). Median LN retrieval was 13 for pancreatoduodenectomy (PD), but only 9 for distal pancreatectomy (DP). Given that PD routinely includes a complete regional lymphadenectomy, a minimum number of LNs to accurately stage patients was not identified. However, for DP, removal of less than seven LNs failed to discriminate 5-year RFS between LN-positive and LN-negative patients (less than seven LNs: 72% vs. 83%, p = 0.198; seven or more LNs: 67% vs. 86%; p = 0.002). CONCLUSIONS: Tumor size ≥ 2 cm, proximal location, moderate differentiation, and Ki-67 ≥ 3% are preoperative factors that predict LN positivity in resected non-functional PanNETs. Given the 9-23% incidence of LN metastases in patients without such risk factors, routine regional lymphadenectomy should be considered. PD inherently includes sufficient LN retrieval, while DP should aim to remove seven or more LNs for accurate staging.
doi: https://doi.org/10.1245/s10434-019-07367-y
- Tspan8 is expressed in breast cancer and regulates E-cadherin/catenin signalling and metastasis accompanied by increased circulating extracellular vesicles
The Journal of pathology 2019 Aug;248(4):421-437
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30982971
Tspan8 exhibits a functional role in many cancer types including pancreatic, colorectal, oesophagus carcinoma, and melanoma. We present a first study on the expression and function of Tspan8 in breast cancer. Tspan8 protein was present in the majority of human primary breast cancer lesions and metastases in the brain, bone, lung, and liver. In a syngeneic rat breast cancer model, Tspan8+ tumours formed multiple liver and spleen metastases, while Tspan8- tumours exhibited a significantly diminished ability to metastasise, indicating a role of Tspan8 in metastases. Addressing the underlying molecular mechanisms, we discovered that Tspan8 can mediate up-regulation of E-cadherin and down-regulation of Twist, p120-catenin, and β-catenin target genes accompanied by the change of cell phenotype, resembling the mesenchymal-epithelial transition. Furthermore, Tspan8+ cells exhibited enhanced cell-cell adhesion, diminished motility, and decreased sensitivity to irradiation. As a regulator of the content and function of extracellular vesicles (EVs), Tspan8 mediated a several-fold increase in EV number in cell culture and the circulation of tumour-bearing animals. We observed increased protein levels of E-cadherin and p120-catenin in these EVs; furthermore, Tspan8 and p120-catenin were co-immunoprecipitated, indicating that they may interact with each other. Altogether, our findings show the presence of Tspan8 in breast cancer primary lesion and metastases and indicate its role as a regulator of cell behaviour and EV release in breast cancer. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
doi: https://doi.org/10.1002/path.5281
- Laparoscopic Complete Mesocolic Excision for Double Flexural Colon Cancers
Annals of surgical oncology 2019 Aug;26(8):2516
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30927197
BACKGROUND: Laparoscopic complete mesocolic excision (CME) for hepatic or splenic flexural colon cancer is considered technically demanding. The double (hepatic and splenic) flexural colon cancers are rare, and the laparoscopic CME procedure for such disease is not standardized. METHODS: This video presents laparoscopic CME for double (hepatic and splenic) flexural colon cancers using a medial and cranial approach. RESULTS: The patient was a 60-year-old woman with the diagnosis of splenic flexure cancer (cT4N1M0) and hepatic flexure cancer (cT3N0M0). Laparoscopic subtotal colectomy was performed. First, the left colic artery was divided at its origin, and the inferior mesenteric vein also was divided at the same level. The descending mesocolon was widely separated from the retroperitoneal tissues using a medial approach. Then, lymph node dissection along the surgical trunk was performed using a cranial approach. Finally, the transverse mesocolon was divided at the inferior border of the pancreas, and CME was achieved. The specimen was extracted through a small incision at the umbilicus, and side-to-side ileo-sigmoid anastomosis was performed extracorporeally. CONCLUSIONS: The approach presented in the video might be useful for standardization of laparoscopic CME for double flexural colon cancers.
doi: https://doi.org/10.1245/s10434-019-07329-4
- Response to Comment on “Letter to Editor Re Manuscript by Bannone et al.” Ann Surg. 2018 Dec 20
Annals of surgery 2019 Aug;270(2):e60-e61
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30870179
doi: https://doi.org/10.1097/SLA.0000000000003259
- Clear Cell Variant of Solid Pseudopapillary Neoplasm of the Pancreas: A Report of a Rare Variant and Review of the Literature
International journal of surgical pathology 2019 Aug;27(5):535-540
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30845855
The clear cell variant of solid pseudopapillary neoplasm (ccSPN) of the pancreas was first described in 2006. In this article, we report a case of this rare variant and review the few published reports. Both the current and previous reports show that ccSPN has several morphologic differences from conventional SPN, including clear vacuoles, fewer pseudopapillary formations, more solid/diffuse architecture, less hemorrhage, and fewer cholesterol clefts. Some of these features peculiar to ccSPN, such as solid/diffuse architecture, have been proposed to suggest aggressive behavior, though reports of ccSPN are rare and often have limited clinical follow-up. ccSPN also appears to occur more frequently in males than conventional SPNs. These clinical and pathologic features lead to unique set of differential diagnostic considerations for ccSPN, including metastatic renal cell carcinoma, perivascular epithelial cell tumor, and clear cell variants of other carcinomas. These unique features, atypical differential, and uncertain prognostic ramifications all make ccSPN an important variant to be aware of and report.
doi: https://doi.org/10.1177/1066896919833790
- Benchmarks in Pancreatic Surgery: A Novel Tool for Unbiased Outcome Comparisons
Annals of surgery 2019 Aug;270(2):211-218
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30829701
OBJECTIVE: To use the concept of benchmarking to establish robust and standardized outcome references after pancreatico-duodenectomy (PD). BACKGROUND: Best achievable results after PD are unknown. Consequently, outcome comparisons among different cohorts, centers or with novel surgical techniques remain speculative. METHODS: This multicenter study analyzes consecutive patients (2012-2015) undergoing PD in 23 international expert centers in pancreas surgery. Outcomes in patients without significant comorbidities and major vascular resection (benchmark cases) were analyzed to establish 20 outcome benchmarks for PD. These benchmarks were tested in a cohort with a poorer preoperative physical status (ASA class ≥3) and a cohort treated by minimally invasive approaches. RESULTS: Two thousand three hundred seventy-five (38%) low-risk cases out of a total of 6186 PDs were analyzed, disclosing low in-hospital mortality (≤1.6%) but high morbidity, with a 73% benchmark morbidity rate cumulated within 6 months following surgery. Benchmark cutoffs for pancreatic fistulas (B-C), severe complications (≥ grade 3), and failure-to-rescue rate were 19%, 30%, and 9%, respectively. The ASA ≥3 cohort showed comparable morbidity but a higher in hospital-mortality (3% vs 1.6%) and failure-to-rescue rate (16% vs 9%) than the benchmarks. The proportion of benchmark cases performed varied greatly across centers and continents for both open (9%-93%) and minimally invasive (11%-62%) PD. Centers operating mostly on complex PD cases disclosed better results than those with a majority of low-risk cases. CONCLUSION: The proposed outcome benchmarks for PD, established in a large-scale international patient cohort and tested in 2 different cohorts, may allow for meaningful comparisons between different patient cohorts, centers, countries, and surgical techniques.
doi: https://doi.org/10.1097/SLA.0000000000003223
- The Impact of Preoperative Immune Modulating Nutrition on Outcomes in Patients Undergoing Surgery for Gastrointestinal Cancer: A Systematic Review and Meta-analysis
Annals of surgery 2019 Aug;270(2):247-256
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30817349
OBJECTIVE: To define the influence of preoperative immune modulating nutrition (IMN) on postoperative outcomes in patients undergoing surgery for gastrointestinal cancer. BACKGROUND: Although studies have shown that perioperative IMN may reduce postoperative infectious complications, many of these have included patients with benign and malignant disease, and the optimal timing of such an intervention is not clear. METHODS: The Embase, Medline, and Cochrane databases were searched from 2000 to 2018, for prospective randomized controlled trials evaluating preoperative oral or enteral IMN in patients undergoing surgery for gastrointestinal cancer. The primary endpoint was the development of postoperative infectious complications. Secondary endpoints included postoperative noninfectious complications, length of stay, and up to 30-day mortality. The analysis was performed using RevMan v5.3 software. RESULTS: Sixteen studies reporting on 1387 patients (715 IMN group, 672 control group) were included. Six of the included studies reported on a mixed population of patients undergoing all gastrointestinal cancer surgery. Of the remaining, 4 investigated IMN in colorectal cancer surgery, 2 in pancreatic surgery, and another 2 in patients undergoing surgery for gastric cancer. There was 1 study each on liver and esophageal cancer. The formulation of nutrition used in all studies in the treated patients was Impact (Novartis/Nestlé), which contains ω-3 fatty acids, arginine, and nucleotides. Preoperative IMN in patients undergoing surgery for gastrointestinal cancer reduced infectious complications [odds ratio (OR) 0.52, 95% confidence interval (CI) 0.38-0.71, P < 0.0001, I = 16%, n = 1387] and length of hospital stay (weighted mean difference -1.57 days, 95% CI -2.48 to -0.66, P = 0.0007, I = 34%, n = 995) when compared with control (isocaloric isonitrogeneous feed or normal diet). It, however, did not affect noninfectious complications (OR 0.98, 95% CI 0.73-1.33, P = 0.91, I = 0%, n = 1303) or mortality (OR 0.55, 95% CI 0.18-1.68, P = 0.29, I = 0%, n = 955). CONCLUSION: Given the significant impact on infectious complications and a tendency to shorten length of stay, preoperative IMN should be encouraged in routine practice in patients undergoing surgery for gastrointestinal cancer.
doi: https://doi.org/10.1097/SLA.0000000000003256
- [Microcystic serous cystadenoma: An uncommon neoplasm of pancreas. Report of two cases]
Annales de pathologie 2019 Aug;39(4):292-296
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30711334
Microcystic variant of serous cystadenoma of the pancreas is a rare neoplasm; essentially located in the body or tail of the pancreas and associated with the von Hippel-Lindau. Often, patients are asymptomatic and the neoplasm is incidentally discovered. Usually radiographic manifestations are characteristic. Histopathological examination revealed uniform clear cuboidal cells; they can be confused with other clear cell neoplasms like renal cell carcinomas, well-differentiated neuroendocrine tumors and solid pseudopapillary tumors of the pancreas. Immunohistochemistry can be help to establish the diagnosis and to remove differential diagnosis. Serous cystadenoma is a benign neoplasm whose prognosis is excellent. We herein report two cases of microcystic serous cystadenomas of the pancreas diagnosed in two asymptomatic women and review analysis in the literature to remind the main features of this lesion and the main differential diagnosis.
doi: https://doi.org/10.1016/j.annpat.2018.12.007
- Response to Comment on “Characterization and Optimal Management of High-risk Pancreatic Anastomoses During Pancreatoduodenectomy: Response to Goussous and Cunningham”
Annals of surgery 2019 Aug;270(2):e58-e59
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30499813
doi: https://doi.org/10.1097/SLA.0000000000003121
- Comment on “Interpreting Clinical Benefits of Neoadjuvant Chemoradiation With Gemcitabine Versus Upfront Surgery in Patients With Borderline Resectable Pancreatic Cancer (BRPC)”
Annals of surgery 2019 Aug;270(2):e48-e50
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30499804
doi: https://doi.org/10.1097/SLA.0000000000003115
- DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth
Gut 2019 08;68(8):1465-1476
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30343272
BACKGROUND AND AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumour with a poor prognosis using current treatments. Targeted therapies may offer a new avenue for more effective strategies. Dual-specificity tyrosine regulated kinase 1A (DYRK1A) is a pleiotropic kinase with contradictory roles in different tumours that is uncharacterised in PDAC. Here, we aimed to investigate the role of DYRK1A in pancreatic tumorigenesis. DESIGN: We analysed DYRK1A expression in PDAC genetic mouse models and in patient samples. DYRK1A function was assessed with knockdown experiments in pancreatic tumour cell lines and in PDAC mouse models with genetic reduction of Dyrk1a dosage. Furthermore, we explored a mechanistic model for DYRK1A activity. RESULTS: We showed that DYRK1A was highly expressed in PDAC, and that its protein level positively correlated with that of c-MET. Inhibition of DYRK1A reduced tumour progression by limiting tumour cell proliferation. DYRK1A stabilised the c-MET receptor through SPRY2, leading to prolonged activation of extracellular signal-regulated kinase signalling. CONCLUSIONS: These findings reveal that DYRK1A contributes to tumour growth in PDAC, at least through regulation of c-MET accumulation, suggesting that inhibition of DYRK1A could represent a novel therapeutic target for PDAC.
doi: https://doi.org/10.1136/gutjnl-2018-316128
- A Prospective, Randomized Phase II Study of Adjuvant Gemcitabine Versus S-1 After Major Hepatectomy for Biliary Tract Cancer (KHBO 1208): Kansai Hepato-Biliary Oncology Group
Annals of surgery 2019 Aug;270(2):230-237
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30339627
OBJECTIVE: To evaluate each arm independently and compare adjuvant gemcitabine (GEM) and S-1 chemotherapy after major hepatectomy (hemihepatectomy or trisectionectomy) for biliary tract cancer (BTC). BACKGROUND: Standardized adjuvant therapy is not performed after major hepatectomy for BTC, and we determined the recommended dose in the former study (KHBO1003). METHODS: We performed a multicenter, randomized phase II study. The primary measure was 1-year recurrence-free survival (RFS); the secondary measures were other RFS, overall survival (OS), and others. The following 6-month adjuvant chemotherapy was administered within 12 weeks of R0/1: GEM (1000 mg/m) every 2 weeks; or S-1 (80 mg/m/d) for 28 days every 6 weeks. Thirty-five patients were assigned to each arm (alpha error, 10%; beta error, 20%). RESULTS: No patients were excluded for the per-protocol analysis. There were no statistically significant differences in the patient characteristics of the 2 arms. The 1-year RFS and 1-year OS rates of the GEM arm were 51.4% and 80.0%, respectively, whereas those of the S-1 group were 62.9% and 97.1%. The comparison of the 2 arms revealed that 2-year RFS rate, 1 and 2-year OS rates, and OS curve of the S-1 arm were superior to GEM. With regard to OS, the hazard ratio of the S-1 group was 0.477 (90% confidence interval 0.245-0.927). CONCLUSION: The comparison of the survival of the 2 groups revealed that adjuvant S-1 therapy may be superior to adjuvant GEM therapy after major hepatectomy for BTC.
doi: https://doi.org/10.1097/SLA.0000000000002865
- Response to Comment on “The Virtual Hepatectomy Changed the Practice of Liver Surgery: More Details, More Significance”
Annals of surgery 2019 Aug;270(2):e33
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30138165
doi: https://doi.org/10.1097/SLA.0000000000003009
- Determinants of Severity in Acute Pancreatitis: A Nation-wide Multicenter Prospective Cohort Study
Annals of surgery 2019 Aug;270(2):348-355
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29672416
OBJECTIVE: The aim of this study was to compare and validate the different classifications of severity in acute pancreatitis (AP) and to investigate which characteristics of the disease are associated with worse outcomes. SUMMARY OF BACKGROUND DATA: AP is a heterogeneous disease, ranging from uneventful cases to patients with considerable morbidity and high mortality rates. Severity classifications based on legitimate determinants of severity are important to correctly describe the course of disease. METHODS: A prospective multicenter cohort study involving patients with AP from 23 hospitals in Spain. The Atlanta Classification (AC), Revised Atlanta Classification (RAC), and Determinant-based Classification (DBC) were compared. Binary logistic multivariate analysis was performed to investigate independent determinants of severity. RESULTS: A total of 1655 patients were included; 70 patients (4.2%) died. RAC and DBC were equally superior to AC for describing the clinical course of AP. Although any kind of organ failure was associated with increased morbidity and mortality, persistent organ failure (POF) was the most significant determinant of severity. All local complications were associated with worse outcomes. Infected pancreatic necrosis correlated with high morbidity, but in the presence of POF, it was not associated to higher mortality when compared with sterile necrotizing pancreatitis. Exacerbation of previous comorbidity was associated with increased morbidity and mortality. CONCLUSION: The RAC and DBC both signify an advance in the description and differentiation of AP patients. Herein, we describe the complications of the disease independently associated to morbidity and mortality. Our findings are valuable not only when designing future studies on AP but also for the improvement of current classifications.
doi: https://doi.org/10.1097/SLA.0000000000002766
- Survival in Locally Advanced Pancreatic Cancer After Neoadjuvant Therapy and Surgical Resection
Annals of surgery 2019 Aug;270(2):340-347
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29596120
OBJECTIVE: The aim of the study was to identify the survival of patients with locally advanced pancreatic cancer (LAPC) and assess the effect of surgical resection after neoadjuvant therapy on patient outcomes. BACKGROUND: An increasing number of LAPC patients who respond favorably to neoadjuvant therapy undergo surgical resection. The impact of surgery on patient survival is largely unknown. MATERIALS AND METHODS: All LAPC patients who presented to the institutional pancreatic multidisciplinary clinic (PMDC) from January 2013 to September 2017 were included in the study. Demographics and clinical data on neoadjuvant treatment and surgical resection were documented. Primary tumor resection rates after neoadjuvant therapy and overall survival (OS) were the primary study endpoints. RESULTS: A total of 415 LAPC patients were included in the study. Stratification of neoadjuvant therapy in FOLFIRINOX-based, gemcitabine-based, and combination of the two, and subsequent outcome comparison did not demonstrate significant differences in OS of 331 non-resected LAPC patients (P = 0.134). Eighty-four patients underwent resection of the primary tumor (20%), after a median duration of 5 months of neoadjuvant therapy. FOLFIRINOX-based therapy and stereotactic body radiation therapy correlated with increased probability of resection (P = 0.006). Resected patients had better performance status, smaller median tumor size (P = 0.029), and lower median CA19-9 values (P < 0.001) at PMDC. Patients who underwent surgical resection had significant higher median OS compared with those who did not (35.3 vs 16.3 mo, P < 0.001). The difference remained significant when non-resected patients were matched for time of neoadjuvant therapy (19.9 mo, P < 0.001). CONCLUSIONS: Surgical resection of LAPC after neoadjuvant therapy is feasible in a highly selected cohort of patients (20%) and is associated with significantly longer median overall survival.
doi: https://doi.org/10.1097/SLA.0000000000002753
- The cost of endoscopic treatment for walled-off pancreatic necrosis
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31383574
BACKGROUND: Use of minimally invasive techniques has reduced mortality in walled-off pancreatic necrosis (WON) but may be costly. The aim of this study was to evaluate the actual costs associated with the endoscopic management of patients with WON. METHODS: We included a retrospective cohort of WON patients treated with endoscopic, transgastric drainage and necrosectomy (ETDN) during 2013-2014. Costs were calculated for six sub-areas based on a micro-costing model. Students T-test and non-parametric analysis of variance were performed to evaluate costs in relation to disease etiology and outcome. RESULTS: We included 58 patients (50% men, median age 57 years). The most common etiologies were gallstones (57%) and alcohol (19%). Nine patients (16%) died during admission. The median length of stay was 50 days (IQR 31 days). Eighteen patients (31%) needed treatment in our intensive care unit with a median length of stay of 16 days (IQR 31 days). The mean costs and standard deviation of costs (SD) per patient were: diagnostic imaging $2,431 ($2,301), laboratory tests $3,579 ($2,477), blood products $982 ($1,734), endoscopic treatment $3,794 ($1,777), medicine $5,440 ($6,656), and ward cost $41,260 ($35,854). The mean total cost was $57,486 ($46,739). Post-ERCP pancreatitis and mortality predicted higher costs. CONCLUSIONS: This study sheds light on the different costs associated with endoscopic treatment of WON. As nearly three quarters of the costs are related to ward care, initiatives aimed at reducing the length of hospital stay may have a great impact on making endoscopic treatment more cost effective.
doi: https://doi.org/10.1016/j.pan.2019.07.042
- Coexisting pancreatic serous cystadenoma and pancreatic ductal adenocarcinoma: A cytological-pathologic correlation with literature review
Annals of diagnostic pathology 2019 Jul;42():87-91
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31382079
Pancreatic serous cystadenoma (SCA) is a benign neoplastic lesion with a distinctive gross and microscopic appearance consisting of numerous thin-walled cysts lined by uniform epithelial cells with clear cytoplasm and small nuclei. The vast majority of serous cystadenomas are benign. Pancreatic SCA has rarely been reported in association with other pancreatic lesions. We present a challenging case in which a cystic and solid pancreatic mass was identified on imaging studies. FNA was performed and showed clusters of atypical cells with significant nuclear pleomorphism (>4:1), disorganized, overlapping nuclei, and prominent nucleoli. The FNA diagnosis was positive for malignancy, consistent with adenocarcinoma. The patient underwent neoadjuvant therapy and pancreaticoduodenectomy. Final pathology showed a serous cystadenoma associated with small foci of high-grade PanIN. The lack of invasive adenocarcinoma in the resection specimen was most likely due to complete response of the tumor to neoadjuvant chemoradiation therapy, but it is also possible that only high-grade PanIN was present initially. To our knowledge, this is the first reported case of SCA and high grade PanIN/PDAC that was assessed by FNA. We discuss the cytologic differential diagnosis and how to avoid potential pitfalls highlighted by this case.
doi: https://doi.org/10.1016/j.anndiagpath.2019.07.006
- The role of abdominal drainage in pancreatic resection - A multicenter validation study for early drain removal
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31378583
BACKGROUND: Abdominal drainage and the timing of drain removal in patients undergoing pancreatic resection are under debate. Early drain removal after pancreatic resection has been reported to be safe with a low risk for clinical relevant postoperative pancreatic fistula (CR-POPF) when drain amylase on POD1 is < 5000U/L. The aim of this study was to validate this algorithm in a large national cohort. METHODS: Patients registered in the Dutch Pancreatic Cancer Audit (2014-2016) who underwent pancreatoduodenectomy, distal pancreatectomy or enucleation were analysed. Data on post-operative drain amylase levels, drain removal, postoperative pancreatic fistulae were collected. Univariate and multivariate analysis using a logistic regression model were performed. The primary outcome measure was grade B/C pancreatic fistula (CR-POPF). RESULTS: Among 1402 included patients, 433 patients with a drain fluid amylase level of <5000U/L on POD1, 7% developed a CR-POPF. For patients with an amylase level >5000U/L the CR-POPF rate was 28%. When using a cut-off point of 2000U/L or 1000U/L during POD1-3, the CR-POPF rates were 6% and 5% respectively. For patients with an amylase level of >2000U/L and >1000UL during POD 1-3 the CR-POPF rates were 26% and 22% respectively (n = 223). Drain removal on POD4 or thereafter was associated with more complications (p = 0.004). Drain amylase level was shown to be the most statistically significant predicting factor for CR-POPF (Wald = 49.7; p < 0.001). CONCLUSION: Our data support early drain removal after pancreatic resection. However, a cut-off of 5000U/L drain amylase on POD1 was associated with a relatively high CR-POPF rate of 7%. A cut-off point of 1000U/L during POD1-3 resulted in 5% CR-POPF and might be a safer alternative.
doi: https://doi.org/10.1016/j.pan.2019.07.041
- Factors predicting readmission within 30 days of acute pancreatitis attack: A prospective study
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31378581
doi: https://doi.org/10.1016/j.pan.2019.07.044
- Intraductal oncocytic papillary neoplasm of the pancreas: A systematic review
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31375434
BACKGROUND: Intraductal oncocytic papillary neoplasm of the pancreas (IOPN-P) is a rare subtype of intraductal papillary mucinous neoplasm (IPMN). This study was performed to summarize the clinicopathological features and management of IOPN-P. METHODS: English-language articles were searched from MEDLINE and EMBASE from the first report of IOPN-P in 1996 until 1 May 2019 following the methodology in the PRISMA guidelines. RESULTS: In total, 66 patients from 24 full articles were included in the final data analysis. The patients’ average age was 61 years, and the male/female ratio was 1. Most lesions were large (average size, 5.50 cm), located in the pancreatic head, and found either incidentally or by uncharacteristic abdominal symptoms. IOPN-P was usually a cystic and solid lesion with or without mural nodules on radiological examination. A definitive diagnosis was often acquired from fine needle aspiration biopsy or postoperative pathology. All tumors were diagnosed as carcinoma in situ or minimally invasive carcinoma, necessitating surgical resection. The prognosis of IOPN-P was better than that of other IPMN subtypes, even when metastasis occurred. Recurrence after surgical resection of IOPN-P was rare. CONCLUSIONS: IOPN-P is rare among IPMN subtypes with unique pathological characteristics. Because of the nontypical symptoms and radiological findings, a definitive preoperative diagnosis usually depends on multimodal examinations. Management and surveillance of IOPN-P after surgical resection should be differentiated from those of other pancreatic benign cystic lesions because of its relative malignancy, but IOPN-P should also be differentiated from other IPMN subtypes and malignant cystic tumors because of its favorable prognosis.
doi: https://doi.org/10.1016/j.pan.2019.07.040
- Rosai-Dorfman Disease of the Pancreas Shows Significant Histologic Overlap With IgG4-related Disease
The American journal of surgical pathology 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31368911
Rosai-Dorfman disease (RDD) is a rare entity characterized by proliferating S100-positive histiocytes. Originally described in lymph nodes, it can involve extranodal sites. Pancreatic involvement is rare, with <10 cases previously reported. Recent studies demonstrate a possible overlap between RDD and the more common IgG4-related disease (IRD), which could further complicate pathologic diagnosis. We describe distinct morphologic characteristics as well as overlapping histologic features of IRD in 5 cases of pancreatic RDD at our institution and compare these to a cohort of nonpancreatic extranodal RDD cases. All pancreatic cases were mass forming and had spindled patterns of elongated histiocytes with smaller areas of more classical appearing RDD; all cases had areas of storiform fibrosis and dense lymphoplasmacytic infiltrates with no increase in IgG4-positive plasma cells, and all cases had some degree of vasculitis (4 cases had obliterative vasculitis). Thirteen nonpancreatic extranodal RDD cases had dense lymphoplasmacytic infiltrates; most (85%) had some fibrosis with 46% showing storiform fibrosis, 85% had vasculitis with 31% demonstrating obliterative vasculitis and 2 cases had increased IgG4 staining. Extranodal (pancreatic and nonpancreatic) RDD often shows overlapping morphologic features with IRD, including lymphoplasmacytic inflammation, storiform fibrosis with elongated histiocytes and vasculitis. This can create a diagnostic challenge in the pancreas where IRD is more commonly encountered. Pathologists need to be aware that RDD can occur in the pancreas and should include RDD in the differential of any mass forming pancreatic lesion in which morphologic features of IRD are present.
doi: https://doi.org/10.1097/PAS.0000000000001334
- ZEB1 promotes inflammation and progression towards inflammation-driven carcinoma through repression of the DNA repair glycosylase MPG in epithelial cells
Gut 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31366457
OBJECTIVE: Chronic inflammation is a risk factor in colorectal cancer (CRC) and reactive oxygen species (ROS) released by the inflamed stroma elicit DNA damage in epithelial cells. We sought to identify new drivers of UC and inflammatory CRC. DESIGN: The study uses samples from patients with UC, mouse models of colitis and CRC and mice deficient for the epithelial-to-mesenchymal transition factor ZEB1 and the DNA repair glycosylase N-methyl-purine glycosylase (MPG). Samples were analysed by immunostaining, qRT-PCR, chromatin immunoprecipitation assays, microbiota next-generation sequencing and ROS determination. RESULTS: ZEB1 was induced in the colonic epithelium of UC and of mouse models of colitis. Compared with wild-type counterparts, Zeb1-deficient mice were partially protected from experimental colitis and, in a model of inflammatory CRC, they developed fewer tumours and exhibited lower levels of DNA damage (8-oxo-dG) and higher expression of MPG. Knockdown of ZEB1 in CRC cells inhibited 8-oxo-dG induction by oxidative stress (H2O2) and inflammatory cytokines (interleukin (IL)1β). ZEB1 bound directly to the MPG promoter whose expression inhibited. This molecular mechanism was validated at the genetic level and the crossing of Zeb1-deficient and Mpg-deficient mice reverted the reduced inflammation and tumourigenesis in the former. ZEB1 expression in CRC cells induced ROS and IL1β production by macrophages that, in turn, lowered MPG in CRC cells thus amplifying a positive loop between both cells to promote DNA damage and inhibit DNA repair. CONCLUSIONS: ZEB1 promotes colitis and inflammatory CRC through the inhibition of MPG in epithelial cells, thus offering new therapeutic strategies to modulate inflammation and inflammatory cancer.
doi: https://doi.org/10.1136/gutjnl-2018-317294
- Actual 10-Year Survival After Surgical Microwave Ablation for Hepatocellular Carcinoma: A Single-Center Experience in Japan
Annals of surgical oncology 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31359277
BACKGROUND: Little evidence exists regarding long-term survival after microwave ablation for hepatocellular carcinoma (HCC). The aim of this study is to determine actual 10-year survival and clarify the clinicopathological features of patients surviving ≥ 10 years after surgical microwave ablation. PATIENTS AND METHODS: This retrospective study identified 459 patients who underwent surgical microwave ablation for HCC with curative intent between 2001 and 2008. We compared 100 patients who survived ≥ 10 years with 321 patients who died within 10 years. RESULTS: Median overall survival and recurrence-free survival rates were 5.5 and 2.4 years, respectively. The actual 10-year overall survival rate was 23.8%, and the actual 10-year recurrence-free survival rate was 8.1%. Multivariate analysis showed that age > 70 years [odds ratio 1.87, P = 0.029], hepatitis C virus positivity (OR 2.30, P = 0.004), Child-Pugh class B (OR 3.28, P = 0.003), and platelet count < 10 × 104 /µL (OR 1.93, P = 0.033) were independent risk factors for actual 10-year survival. During 10-year follow-up, 66% of the ≥ 10-year survivors developed recurrence, and 91% of these patients underwent further curative treatment, including hepatic resection or local ablation, for HCC recurrence. CONCLUSION: Ten-year survival after surgical microwave ablation for HCC can be expected in approximately 24% of patients, even though nearly 2/3 of our 10-year survival patients experienced recurrence. Close postoperative follow-up and further curative treatment for recurrence are important for improving long-term survival.
doi: https://doi.org/10.1245/s10434-019-07646-8
- Characterization and comparison of GITR expression in solid tumors
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31358539
PURPOSE: Determine the differential effect of a FcgR-binding, mIgG2a anti-GITR antibody in mouse tumor modelsand characterize the tumor microenvironment for the frequency of GITR expression in T cell subsets from seven different human solid tumors. EXPERIMENTAL DESIGN: For mouse experiments, wildtype C57BL/6 mice were subcutaneously injected with MC38 cells or B16 cells, and BALB/c mice were injected with CT26 cells. Mice were treated with the anti-mouse GITR agonist antibody 21B6, and tumor burden and survival were monitored. GITR expression was evaluated at the single cell level using flow cytometry (FC). 213 samples were evaluated for GITR expression by immunohistochemistry (IHC), 63 by FC and 170 by both in seven human solid tumors: advanced hepatocellular carcinoma, non-small cell lung cancer, renal cell carcinoma, pancreatic carcinoma, head and neck carcinoma, melanoma, and ovarian carcinoma. RESULTS: The therapeutic benefit of 21B6 was greatest in CT26 followed by MC38, and was least in the B16 tumor model. The frequency of CD8 T cells and effector CD4 T cells within the immune infiltrate correlated with response to treatment with GITR antibody. Analysis of clinical tumor samples showed that non-small cell lung cancer, renal cell carcinoma, and melanoma had the highest proportions of GITR-expressing cells and highest per-cell density of GITR expression on CD4-positive Foxp3 positive Tregs. IHC and FC data showed similar trends with a good correlation between both techniques. CONCLUSIONS: Human tumor data suggest that NSCLC, RCC, and melanoma should be the tumor subtypes prioritized for anti-GITR therapy development.
doi: https://doi.org/10.1158/1078-0432.CCR-19-0289
- Fungal sinusitis in simultaneous pancreas-kidney transplant
Journal of clinical pathology 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31358535
doi: https://doi.org/10.1136/jclinpath-2018-205258
- New Nodal Staging for Primary Pancreatic Neuroendocrine Tumors: A Multi-institutional and National Data Analysis
Annals of surgery 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31356277
OBJECTIVE: To determine the prognostic role of metastatic lymph node (LN) number and the minimal number of LNs for optimal staging of patients with pancreatic neuroendocrine tumors (pNETs). BACKGROUND: Prognosis relative to number of LN metastasis (LNM), and minimal number of LNs needed to evaluate for accurate staging, have been poorly defined for pNETs. METHODS: Number of LNM and total number of LN evaluated (TNLE) were assessed relative to recurrence-free survival (RFS) and overall survival (OS) in a multi-institutional database. External validation was performed using Surveillance, Epidemiology and End Results (SEER) registry. RESULTS: Among 854 patients who underwent resection, 233 (27.3%) had at least 1 LNM. Patients with 1, 2, or 3 LNM had a comparable worse RFS versus patients with no nodal metastasis (5-year RFS, 1 LNM 65.6%, 2 LNM 68.2%, 3 LNM 63.2% vs 0 LNM 82.6%; all P < 0.001). In contrast, patients with ≥4 LNM (proposed N2) had a worse RFS versus patients who either had 1 to 3 LNM (proposed N1) or node-negative disease (5-year RFS, ≥4 LNM 43.5% vs 1-3 LNM 66.3%, 0 LNM 82.6%; all P < 0.05) [C-statistics area under the curve (AUC) 0.650]. TNLE ≥8 had the highest discriminatory power relative to RFS (AUC 0.713) and OS (AUC 0.726) among patients who had 1 to 3 LNM, and patients who had ≥4 LNM in the multi-institutional and SEER database (n = 2764). CONCLUSIONS: Regional lymphadenectomy of at least 8 lymph nodes was necessary to stage patients accurately. The proposed nodal staging of N0, N1, and N2 optimally staged patients.
doi: https://doi.org/10.1097/SLA.0000000000003478
- Left-sided Portal Hypertension After Pancreaticoduodenectomy With Resection of the Portal Vein/Superior Mesenteric Vein Confluence in Patients With Pancreatic Cancer: A Project Study by the Japanese Society of Hepato-Biliary-Pancreatic Surgery
Annals of surgery 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31356273
OBJECTIVE: The aim of this study was to evaluate how often left-sided portal hypertension (LPH) develops and how LPH affects the long-term outcomes of patients with pancreatic cancer treated with pancreaticoduodenectomy (PD) and resection of the portal vein (PV)/superior mesenteric vein (SMV) confluence. SUMMARY BACKGROUND DATA: Little is known about LPH after PD with resection of the PV/SMV confluence. METHODS: Overall, 536 patients who underwent PD with PV/SMV resection were enrolled. Among them, we mainly compared the SVp group [n=285; the splenic vein (SV) was preserved] and the SVr group (n = 227; the SV was divided and not reconstructed). RESULTS: The incidence of variceal formation in the SVr group increased until 3 years after PD compared with that in the SVp group (38.7% vs 8.3%, P < 0.001). Variceal bleeding occurred in the SVr group (n = 9: 4.0%) but not in the SVp group (P < 0.001). In the multivariate analysis, the risk factors for variceal formation were liver disease, N factor, conventional PD, middle colic artery resection, and SV division. The only risk factor for variceal bleeding was SV division. The platelet count ratio at 6 months after PD was significantly lower in the SVr group than in the SVp group (0.97 vs 0.82, P < 0.001), and the spleen-volume ratios at 6 and 12 months were significantly higher in the SVr group than in the SVp group (1.38 vs 1.00 and 1.54 vs 1.09; P < 0.001 and P < 0.001, respectively). CONCLUSIONS: PD with SV division causes variceal formation, bleeding, and thrombocytopenia.
doi: https://doi.org/10.1097/SLA.0000000000003487
- Cytology with rapid on-site examination (ROSE) does not improve diagnostic yield of EUS-FNA of pancreatic cystic lesions
Diagnostic cytopathology 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31356003
BACKGROUND: Cytology with rapid on-site evaluation (ROSE) has been shown to increase the diagnostic accuracy of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for solid pancreatic lesions. No data exists on the need for rapid onsite cytology in the evaluation of pancreatic cystic lesions (PCLs). The purpose of this study is to determine whether onsite cytology impacts the diagnostic yield of EUS-FNA of PCLs. METHODS: We prospectively examined all patients with PCLs who underwent EUS-FNA without onsite cytology over a 6-month period and compared this to a historical cohort of patients with PCLs who underwent EUS-FNA with ROSE in the previous 6 months. Comparison was made between the two groups based upon patient demographics, EUS cyst characteristics, and FNA fluid & cytopathology results. RESULTS: A total of 100 EUS-FNA exams for PCLs were identified: 46 with ROSE and 54 without onsite cytology. The majority of cytology findings were negative or nondiagnostic, 87.0% in the ROSE group, 77.8% in the group without onsite cytology. There was no difference using EUS-FNA without onsite cytology compared to ROSE when measuring total diagnostic yield (22.2% vs 13.0%, P = .30), number of nondiagnostic specimens (50% vs 54%, P = .69), and number of needle passes (1.51 vs 1.57, P = .68). CONCLUSIONS: (a) The majority of cytology results from EUS-FNA of cystic lesions are negative or nondiagnostic. (b) Having rapid onsite cytology evaluation of cystic lesions does not affect the number of needle passes nor diagnostic yield and is thus not recommended.
doi: https://doi.org/10.1002/dc.24291
- Oncogenic KRAS Reduces Expression of FGF21 in Acinar Cells to Promote Pancreatic Tumorigenesis in Mice on a High-Fat Diet
Gastroenterology 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31352001
BACKGROUND & AIMS: Obesity is a risk factor for pancreatic cancer. In mice, a high-fat diet (HFD) and expression of oncogenic KRAS lead to development of invasive pancreatic ductal adenocarcinoma (PDAC) by unknown mechanisms. We investigated how oncogenic KRAS regulates the expression of fibroblast growth factor 21 (FGF21), a metabolic regulator that prevents obesity, and the effects of recombinant human FGF21 (rhFGF21) on pancreatic tumorigenesis. METHODS: We performed immunohistochemical analyses of FGF21 levels in human pancreatic tissue arrays, comprising 59 PDAC specimens and 45 non-tumor tissues. We also studied mice with tamoxifen-inducible expression of oncogenic KRAS in acinar cells (KrasG12D/+ mice) and fElasCreERT mice (controls). KrasG12D/+ mice were placed on a HFD or regular chow diet (control) and given injections of rhFGF21 or vehicle; pancreata were collected and analyzed by histology, immunoblots, quantitative PCR, and immunohistochemistry. We measured markers of inflammation in the pancreas, liver, and adipose tissue. Activity of RAS was measured based on the amount of bound GTP. RESULTS: Pancreatic tissues of mice expressed high levels of FGF21 compared with liver. FGF21 and its receptor proteins were expressed by acinar cells. Acinar cells that expressed KrasG12D/+ had significantly lower expression of Fgf21 mRNA, compared with acinar cells from control mice, partly due to downregulation of PPARG expression-a transcription factor that activates Fgf21 transcription. Pancreata from KrasG12D/+ mice on a control diet and given injections of rhFGF21 had reduced pancreatic inflammation, infiltration by immune cells, and acinar-to-ductal metaplasia compared with mice given injections of vehicle. HFD-fed KrasG12D/+ mice given injections of vehicle accumulated abdominal fat, developed extensive inflammation, pancreatic cysts, and high-grade pancreatic intraepithelial neoplasias (PanINs); half the mice developed PDAC with liver metastases. HFD-fed KrasG12D/+ mice given injections of rhFGF21 had reduced accumulation of abdominal fat and pancreatic triglycerides, fewer pancreatic cysts, reduced systemic and pancreatic markers of inflammation, fewer PanINs, and longer survival-only about 12% of mice developed PDACs and none of the mice had metastases. Pancreata from HFD-fed KrasG12D/+ mice given injections of rhFGF21 had lower levels of active RAS than from mice given vehicle. CONCLUSIONS: Normal acinar cells from mice and humans express high levels of FGF21. In mice, acinar expression of oncogenic KRAS significantly reduces FGF21 expression. When these mice are placed on a HFD, they develop extensive inflammation, pancreatic cysts, PanINs, and PDACs, which are reduced by injection of FGF21. FGF21 also reduces the GTP binding capacity of RAS. FGF21 might be used in prevention or treatment of pancreatic cancer.
doi: https://doi.org/10.1053/j.gastro.2019.07.030
- Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer
The New England journal of medicine 2019 07;381(4):317-327
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31157963
BACKGROUND: Patients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib has had antitumor activity in this population. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy. Patients were randomly assigned, in a 3:2 ratio, to receive maintenance olaparib tablets (300 mg twice daily) or placebo. The primary end point was progression-free survival, which was assessed by blinded independent central review. RESULTS: Of the 3315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 to receive olaparib and 62 to receive placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups (median, 18.9 months vs. 18.1 months; hazard ratio for death, 0.91; 95% CI, 0.56 to 1.46; P = 0.68). There was no significant between-group difference in health-related quality of life, as indicated by the overall change from baseline in the global quality-of-life score (on a 100-point scale, with higher scores indicating better quality of life) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (between-group difference, -2.47 points; 95% CI, -7.27 to 2.33). The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group (between-group difference, 16 percentage points; 95% CI, -0.02 to 31); 5% and 2% of the patients, respectively, discontinued the trial intervention because of an adverse event. CONCLUSIONS: Among patients with a germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo. (Funded by AstraZeneca and others; POLO ClinicalTrials.gov number, NCT02184195.).
doi: https://doi.org/10.1056/NEJMoa1903387
- Response to repeat echoendoscopic celiac plexus neurolysis in pancreatic cancer patients: A machine learning approach
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31375433
BACKGROUND: /Objectives: Efficacy of repeat echoendoscopic celiac plexus neurolysis is still unclear. Aim of the study was to assess the efficacy of repeat celiac plexus neurolysis and to build an artificial neural network model able to predict pain response. METHODS: Data regarding 156 patients treated with repeat celiac plexus neurolysis between 2004 and 2019 were reviewed. Artificial neural network and logistic regression models were built to predict pain response after treatment. Performance of the models was expressed in terms of accuracy, positive predictive value, and positive likelihood ratio. RESULTS: Median age was 62 years (range 39-86) and most patients were male (66%) with pre-procedural visual analogue score 7. Fifty-one patients (32.6%) experienced treatment response, of which 6 (3.8%) complete pain suppression. Median duration of pain relief was 6 (2-8) weeks. Tumoral stage, interval from initial to repeat treatment, response to initial neurolysis, and tumor progression between the two treatments resulted as significant predictors of pain response. The performance of the artificial neural network in predicting treatment response was higher than regression model (area under the curve: 0.94, 0.89-0.97 versus 0.85, 0.78-0.89; p < 0.001). Positive predictive value and positive likelihood ratio resulted 90.3% and 19.35, respectively. Classification error rate was 5.7% with the artificial neural network compared to 14.7% of regression model (p < 0.001). These findings were confirmed through ten-fold cross validation. CONCLUSIONS: Pain response following repeat neurolysis is generally less pronounced than after initial treatment. Artificial neural network may help to identify those subjects likely to benefit from repeat neurolysis.
doi: https://doi.org/10.1016/j.pan.2019.07.038
- Characterising the impact of body composition change during neoadjuvant chemotherapy for pancreatic cancer
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31362865
BACKGROUND: Pancreatic Cancer remains a lethal disease for the majority of patients. New chemotherapy agents such as Folfirinox offer therapeutic potential for patients who present with Borderline Resectable disease (BRPC). However, results to date are inconsistent, with factors such as malnutrition limiting successful drug delivery. We sought to determine the prevalence of sarcopenia in BRPC patients at diagnosis, and to quantify body composition change during chemotherapy. METHODS: The diagnostic/restaging CT scans of BRPC patients were analysed. Body composition was measured at L3 using Tomovision Slice-O-Matic™. Total muscle and adipose tissue mass were estimated using validated regression equations. Sarcopenia was defined as per gender- and body mass index (BMI)-specific lumbar skeletal muscle index (LSMI) and muscle attenuation reference values. RESULTS: Seventy-eight patients received neo-adjuvant chemotherapy, and 67 patients underwent restaging CT, at which point a third were deemed resectable. Half were sarcopenic at diagnosis, and sarcopenia was equally prevalent across all BMI categories.. Skeletal muscle and adipose tissue (intra-muscular, visceral and sub-cutaneous) area decreased during chemotherapy (p < 0.0001). Low muscle attenuation was observed in half of patients at diagnosis, and was associated with increased mortality risk. Loss of lean tissue parameters during chemotherapy was associated with an increased mortality risk; specifically fat-free mass, HR 1.1 (95% CI 1.03-1.17, p = 0.003) and skeletal muscle mass, HR 1.21 (95%CI 1.08-1.35, p = 0.001). CONCLUSIONS: Sarcopenia was prevalent in half of patients at the time of diagnosis with BRPC. Low muscle attenuation at diagnosis, coupled with lean tissue loss during chemotherapy, independently increased mortality risk.
doi: https://doi.org/10.1016/j.pan.2019.07.039
- Fine needle aspiration of the liver: a ten-year single institution retrospective review
Human pathology 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31351156
Fine-needle aspiration (FNA) of liver masses is a minimally invasive means of evaluation, with diagnostic accuracy over 85%. Given that most of the recent literature on sampling hepatic tumors was published by radiologists and gastroenterologists, we herein conduct a 10-year retrospective review of a single institution’s cytopathology experience with the diagnosis of liver lesions. Electronic record review of the cytopathology files (CoPathPlus; Cerner Corp.) was conducted for the 10-year interval January 2007 through December 2016. All cytology specimens designated as “liver” and “FNA” were included. Associated concurrent and subsequent surgical pathology and cytopathology cases were identified. All FNA cases were organized into four diagnostic categories: positive for malignancy, atypical, negative for malignancy, and non-diagnostic. There were 713 hepatic FNAs that were categorized as follows: positive for malignancy 467 (65.5%), atypical 49 (6.9%), negative 171 (24.0%) and non-diagnostic 26 (3.6%). Metastatic tumors (95.7%) were more common that primary (4.3%). The top two metastatic primary sites were pancreas (30.1%) and colon (12.7%). A total of 166 (23.2%) cases had concurrent core needle biopsies (CNB). 111 (66.9%) were concordant with the FNA diagnosis. Of the 55 discordant cases, 43 (25.9%) had diagnostic material only on CNB and 12 (7.2%) had diagnostic material only on FNA. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were 93.4%, 96.7%, 98.2%, 84.3%, and 89.3% respectively. Irrespective of endoscopic versus percutaneous approach, hepatic FNA is a sensitive and specific means of identifying metastatic and primary malignancies of the liver.
doi: https://doi.org/10.1016/j.humpath.2019.07.007
- Reappraisal of a 2-Cm Cut-Off Size for the Management of Cystic Pancreatic Neuroendocrine Neoplasms: A Multicenter International Study
Annals of surgery 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31348038
MINI: The characteristics of cystic pancreatic neuroendocrine neoplasms (cPanNENs) are largely unknown, and their clinical management remains unclear; specifically, an observational strategy for asymptomatic cPanNENs ≤2 cm has been proposed by recent guidelines, but evidence is scarce and limited to single institutional series. In this international cohort study of 263 resected cPanNENs from 16 institutions worldwide, a preoperative size >2 cm was independently associated with aggressive behavior both in the whole cohort and in the subset of asymptomatic patients; notably, only 1 of 61 asymptomatic cPanNENs ≤2 cm was aggressive. Based on these results, a watch-and-wait policy for sporadic asymptomatic cPanNENs ≤2 cm seems justified and safe. The aim of this study was to characterize an international cohort of resected cystic pancreatic neuroendocrine neoplasms (cPanNENs) and identify preoperative predictors of aggressive behavior. The characteristics of cPanNENs are unknown and their clinical management remains unclear. An observational strategy for asymptomatic cPanNENs ≤2 cm has been proposed by recent guidelines, but evidence is scarce and limited to single-institutional series. Resected cPanNENs (1995-2017) from 16 institutions worldwide were included. Solid lesions (>50% solid component), functional tumors, and MEN-1 patients were excluded. Aggressiveness was defined as lymph node (LN) involvement, G3 grading, distant metastases, and/or recurrence. Overall, 263 resected cPanNENs were included, among which 177 (63.5%) were >2 cm preoperatively. A preoperative diagnosis of cPanNEN was established in 162 cases (61.6%) and was more frequent when patients underwent endoscopic ultrasound [EUS, odds ratio (OR) 2.69, 95% confidence interval (CI) 1.52-4.77] and somatostatin-receptor imaging (OR 3.681, 95% CI 1.809-7.490), and for those managed in specialized institutions (OR 3.12, 95% CI 1.57-6.21). Forty-one cPanNENs (15.6%) were considered aggressive. In the whole cohort, LN involvement on imaging, age >65 years, preoperative size >2 cm, and pancreatic duct dilation were independently associated with aggressive behavior. In asymptomatic patients, older age and a preoperative size >2 cm remained independently associated with aggressiveness. Only 1 of 61 asymptomatic cPanNENs ≤2 cm displayed an aggressive behavior. The diagnostic accuracy of cPanNENs is increased by the use of EUS and somatostatin-receptor imaging and is higher in specialized institutions. Preoperative size >2 cm is independently associated with aggressive behavior. Consequently, a watch-and-wait policy for sporadic asymptomatic cPanNENs ≤2 cm seems justified and safe for most patients.
doi: https://doi.org/10.1097/SLA.0000000000003508
- Long non-coding RNA PTTG3P functions as an oncogene by sponging miR-383 and up-regulating CCND1 and PARP2 in hepatocellular carcinoma
BMC cancer 2019 Jul;19(1):731
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31340767
BACKGROUND: Emerging evidence indicates that Long non-coding RNAs (LncRNAs) and microRNAs (miRNAs) play crucial roles in tumor progression, including hepatocellular carcinoma (HCC). However, whether there is a crosstalk between LncRNA pituitary tumor-transforming 3 (PTTG3P) and miR-383 in HCC remains unknown. This study is designed to explore the underlying mechanism by which LncRNA PTTG3P sponges miR-383 during HCC progression. METHODS: qPCR and Western blot were used to analyze LncRNA PTTG3P, miR-383 and other target genes’ expression. CCK-8 assay was performed to examine cell proliferation. Annexin V-PE/PI and PI staining were used to analyze cell apoptosis and cell cycle distribution by flow cytometry, respectively. Transwell migration and invasion assays were used to examine cell migration and invasion abilities. An in vivo xenograft study was performed to detect tumor growth. Luciferase reporter assay and RNA pull-down assay were carried out to detect the interaction between miR-383 and LncRNA PTTG3P. RIP was carried out to detect whether PTTG3P and miR-383 were enriched in Ago2-immunoprecipitated complex. RESULTS: In this study, we found that PTTG3P was up-regulated in HCC tissues and cells. Functional experiments demonstrated that knockdown of PTTG3P inhibited cell proliferation, migration and invasion, and promoted cell apoptosis, acting as an oncogene. Mechanistically, PTTG3P upregulated the expression of miR-383 targets Cyclin D1 (CCND1) and poly ADP-ribose polymerase 2 (PARP2) by sponging miR-383, acting as a competing endogenous RNA (ceRNA). The PTTG3P-miR-383-CCND1/PARP2 axis modulated HCC phenotypes. Moreover, PTTG3P also affected the PI3K/Akt signaling pathway. CONCLUSION: The data indicate a novel PTTG3P-miR-383-CCND1/PARP2 axis in HCC tumorigenesis, suggesting that PTTG3P may be used as a potential therapeutic target in HCC.
doi: https://doi.org/10.1186/s12885-019-5936-2
- Age-related morphological changes in the pancreas and their association with pancreatic carcinogenesis
Pathology international 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31339204
Age-related pathological changes in the pancreas have been unclear because they are often minor and nonspecific. However, recent studies have shown that they are closely related to various pathological conditions such as pancreatic cancer and diabetes mellitus. Knowledge of age-related changes is important to determine appropriate prevention, detection, and treatment strategies for various diseases observed in elderly patients. We present a review of the pathological age-related non-neoplastic changes in the exocrine pancreas such as pancreatic fatty replacement, lobulocentric pancreatic atrophy, pancreatic duct ectasia, and metaplasia of exocrine pancreas, as well as changes in islet cells. We have discussed common pancreatic neoplasms in elderly patients, such as pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMNs), and pancreatic ductal adenocarcinoma (PDAC). Age-related pathological changes play a key role in pancreatic carcinogenesis via telomere dysfunction. Further studies are warranted to clarify molecular mechanisms of pancreatic carcinogenesis in elderly patients.
doi: https://doi.org/10.1111/pin.12837
- Morphologic Factors Predict Pain Relief Following Pancreatic Head Resection in Chronic Pancreatitis Description of the Chronic Pancreatitis Pain Relief (CPPR) Score
Annals of surgery 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31348039
OBJECTIVE: This study analyzes the clinicopathologic findings and their impact on outcome of patients so as to identify which patients benefit most from surgical treatment in chronic pancreatitis, especially in regard to pain relief. SUMMARY BACKGROUND DATA: The predominant symptom of chronic pancreatitis is chronic pain resulting in reduced quality of life. It is well known that the main reason for development of the disease is abuse of alcohol and nicotine, but only little data on factors influencing outcome are available. METHODS: One thousand one hundred forty-six consecutive patients who underwent surgery for chronic pancreatitis were included. Clinicopathologic data, including morphology of the pancreas in preoperative diagnostics and the histopathologic results, were evaluated. A long-term follow-up including Quality of Life and pain scores was performed. Additionally, we describe the novel Chronic Pancreatitis Pain Relief Score (CPPR-Score) as a tool for prediction of pain relief. RESULTS: Overall the rate of pain relief was 79.8% after surgery. The presence of an inflammatory mass in the pancreatic head larger than 4 cm (P < 0.001), presence of a dilated main pancreatic duct of over 4 mm (P < 0.001), histopathologically detected severe calcifications (P = 0.001) and severe fibrosis (P < 0.001) as well as ethanol induced disease (P < 0.001) found to be strong independent prognostic factors for pain relief. The CPPR-Score (0-5 points) proved to be a very good predictive score for pain-relief (P < 0.001). CONCLUSIONS: The rate of pain relief after surgical treatment in chronic pancreatitis is high and the commonly used procedures can be performed with acceptable morbidity and mortality. The Chronic Pancreatitis Pain Relief Score allows identifying patients who will benefit most from surgery.
doi: https://doi.org/10.1097/SLA.0000000000003439
- Acinar cell carcinoma of the pancreas with thyroid-like follicular features: first description of a new diagnostic challenging subtype
Virchows Archiv : an international journal of pathology 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31338587
Acinar cell carcinomas (ACCs) of the pancreas are a heterogeneous group of neoplasms showing a wide spectrum of morphological features including acinar, solid, glandular, and trabecular architecture. In addition, uncommon cytological aspects have recently been described and include oncocytic, spindle, clear, and pleomorphic cell types. This wide histological spectrum represents a challenge in the diagnostic task for pathologists. Molecular mechanisms involved in the onset and progression of ACCs are not completely known, but, in general, they differ from those observed in ductal adenocarcinomas or neuroendocrine neoplasms of the pancreas and frequently include alterations in the APC/β-catenin pathway. In the present paper, we describe a new variant of ACC showing thyroid-like follicular features and CTNNB1 mutation. This phenotype needs to be included in the spectrum of morphological presentation of ACC.
doi: https://doi.org/10.1007/s00428-019-02628-3
- Overall survival in patients over 40 years old with surgically resected pancreatic carcinoma: a SEER-based nomogram analysis
BMC cancer 2019 Jul;19(1):726
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31337369
BACKGROUND: The aim of this study was to identify the determinants of overall survival (OS) within patients over 40 years old with surgically resected pancreatic carcinoma (PC), and to develop a nomogram with the intention of OS predicting. METHODS: A total of 6341 patients of 40 years of age or later with surgically resected PC between 2010 and 2015 were enrolled from the Surveillance, Epidemiology, and End Results (SEER) program and randomly assigned into training set (4242 cases) and validation set (2099 cases). A nomogram was constructed for predicting 1-, 2- and 3-years OS based on univairate and multivariate Cox regression. The C-index and calibration plot were adopted to assess the nomogram performance. RESULTS: Our analysis showed that age, location of carcinoma in pancreas, tumor grade, TNM stage, size of carcinoma together with lymph node ratio (LNR) were considered to be independent overall survival predictors. A nomogram based on these six factors was developed with C-index being 0.680 (95%CI: 0.667-0.693). All calibration curves of OS fitted well. The OS curves stratified by nomogram-predicted probability score (≥20, 10-19 and < 10) demonstrated statistically significant difference not only within training set but also in validation set. CONCLUSIONS: The present nomogram for OS predicting can serve as the efficacious survival-predicting model and assist in accurate decision-making for patients over 40 years old with surgically resected PC.
doi: https://doi.org/10.1186/s12885-019-5958-9
- Anticancer immunotherapy by MFAP5 blockade inhibits fibrosis and enhances chemosensitivity in ovarian and pancreatic cancer
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31332047
PURPOSE: Recent studies demonstrate the role of the tumor microenvironment in tumor progression. However, strategies used to overcome the malignant phenotypes of cancer cells modulated by the microenvironment have not been thoroughly explored. In this study, we evaluated the therapeutic efficacy of a newly developed monoclonal antibody targeting microfibril associated protein 5 (MFAP5), which is secreted predominately by CAFs, in ovarian and pancreatic cancer models. EXPERIMENTAL DESIGN: Monoclonal antibodies were developed using human MFAP5 recombinant protein as an antigen in mice and antibodies from hybridoma clones were evaluated for their specificity to human and murine MFAP5. An Octet RED384 system was used to determine the kinetics of binding affinity and the specificity of the antibody clones, which were followed by epitope mapping and functional characterization by in vitro assays. The therapeutic efficacy of a lead anti-MFAP5 antibody clone 130A in tumor suppression was evaluated by ovarian tumor- and pancreatic tumor-bearing mouse models. RESULTS: Three hybridoma clones, which produced antibodies with high affinity and specificity to MFAP5, were selected for functional studies. Antibody clone 130A, which recognizes a common epitope shared between human and murine MFAP5 protein, were further selected for in vivo studies. Results showed that clone 130A down-regulated MFAP5-induced collagen production in CAFs, suppressed intratumoral microvessel leakiness, and enhanced paclitaxel bioavailability in both ovarian and pancreatic cancer mouse models. CONCLUSIONS: These data suggest that MFAP5 blockade using an immunologic approach inhibits fibrosis, induces tumor vessel normalization and enhances chemosensitivity in ovarian and pancreatic cancer, and can be used as a novel therapeutic agent.
doi: https://doi.org/10.1158/1078-0432.CCR-19-0187
- Metastatic low-grade endometrial stromal sarcoma of uterus presenting as a primary pancreatic tumor: case presentation and literature review
Diagnostic pathology 2019 Apr;14(1):30
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31010432
BACKGROUND: Metastatic tumors to the pancreas are uncommon, accounting for approximately 2% of pancreatic malignancies. The most common primary tumors to give rise to pancreatic metastases are carcinomas. CASE PRESENTATION: A 50-year old female patient was investigated for a cause of abdominal discomfort. She had a 2-year history of menorrhagia and dysmenorrhea which was ascribed to a fibroid uterus. On imaging, she was found to have a large solid and cystic mass in the tail of the pancreas. Imaging also confirmed a fibroid uterus. A distal pancreatectomy and splenectomy showed a 9 cm circumscribed mass within, and grossly confined to, the parenchyma of the pancreatic tail. Microscopically, the pancreatic lesion was lobulated, and well-circumscribed, but focally infiltrative. It comprised sheets of uniform spindled to epithelioid cells with round to oval nuclei, coarse to vesicular chromatin, visible nucleoli, nuclear grooves and clear to eosinophilic cytoplasm. Prominent arterioles were identified. The stroma was collagenized in areas. Occasional hemosiderin-laden macrophages were seen, and focal cystic change was present. There was no evidence of nuclear pleomorphism, mitotic activity or necrosis, and there was no evidence of endometriosis despite multiple sections being taken. Immunohistochemistry showed that the tumor cells were positive for CD10, estrogen receptor (ER), progesterone receptor (PR), Wilms tumor-1 (WT-1) and smooth muscle actin (SMA). RNA sequencing detected a PHF1 rearrangement. The morphological, immunohistochemical and molecular features were of a low-grade endometrial stromal sarcoma (LG-ESS). Subsequent total hysterectomy and bilateral salpingo-oophorectomy 3 months later, showed uterine fibroids and a 5 cm low-grade endometrial stromal sarcoma confined to the uterus, with lymphatic invasion. CONCLUSIONS: To the best of our knowledge, this is the first documented case of metastatic endometrial stromal sarcoma of uterus presenting as a primary pancreatic neoplasm. An unexpected extra-uterine location and unusual presentation of ESS may make the diagnosis challenging, despite classic histological features. Morphological, immunohistochemical and molecular findings must be combined to render the correct diagnosis.
doi: https://doi.org/10.1186/s13000-019-0807-3
- [Heterotopic tissue in the gastrointestinal tract]
Der Pathologe 2018 Sep;39(5):402-408
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30105611
Heterotopia of the gastrointestinal tract is a common finding. This is due to the complex embryogenesis and the relative ease to detect heterotopic tissue during endoscopy. The reason for biopsy is mostly to rule out neoplasms or to define specific causes of inflammation. Heterotopic tissue can occur in any location of the gastrointestinal tract. The most frequent are gastric heterotopia, pancreatic heterotopia, and heterotopia of Brunner’s gland. On rare occasions, heterotopic tissue of salivary gland type as well as heterotopias of apocrine glands, thyroid, and prostatic tissue have been described. The most frequently involved organs are the small intestine, in particular the duodenum, the esophagus, and the stomach. Heterotopia of the large bowel occurs exclusively in the rectum. Most heterotopias do not cause symptoms and are easily diagnosed by biopsy and histology. However, depending on location, size, and the kind of underlying heterotopic tissue, they may cause significant complications, such as inflammation, ulceration and perforation, obstruction, intussusception, and severe life-threatening bleeding. Another rare but significant complication is neoplasia. Gastric heterotopias may give rise to pyloric gland adenomas within the bowel or rarely adenocarcinomas of the esophagus. Pancreatic heterotopia can be complicated by ductal type pancreatic adenocarcinomas, by acinus cell carcinomas, by intraductal papillary mucinous neoplasias, and also by endocrine tumors. The present paper summarizes our current knowledge about heterotopias in a topographic clinico-pathological manner.
doi: https://doi.org/10.1007/s00292-018-0466-2
- Systematic Selective Sampling of Cholecystectomy Specimens is Adequate to Detect Incidental Gallbladder Adenocarcinoma
The American journal of surgical pathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31464710
Many gallbladder adenocarcinomas (ACs) are detected incidentally in routine cholecystectomy specimens, yet sampling practices vary when intestinal metaplasia (IM) or dysplasia are found via routine sampling. Our practice has been to submit 5 additional sections when IM is found, but cases with dysplasia are entirely submitted. We sought to determine an appropriate sampling protocol when encountering these findings. We retrospectively identified cholecystectomy specimens with these features over a 26-month period, yielding 48 of 4059 (1%) cases. Four pathologists independently classified the (2 longitudinal and 1 cystic duct margin) original sections into 1 of 3 categories (IM, low-grade dysplasia [LGD] or high-grade dysplasia [HGD]); initial findings were correlated with final diagnoses. Sixteen (33%) cases had additional findings upon further sampling, including LGD (n=10) or HGD (n=4) and AC (n=2). HGD always accompanied malignancy. We prospectively analyzed 39 of 3133 (1%) additional cholecystectomy specimens, initially submitting the same routine sections. We submitted 5 random sections from cases with IM. Cases with LGD were first examined with 1 additional section per centimeter. All remaining tissue was submitted in all of these cases and separately reviewed. Cases with HGD were entirely submitted as both test cases with HGD in initial sections ultimately showed carcinoma. This protocol detected all cases of HGD and AC. Patients with clear cystic duct margins did not experience neoplastic progression, even if dysplasia was present elsewhere. We conclude gallbladders with HGD should be entirely submitted, LGD may be representatively sampled, and routine sampling is adequate for IM.
doi: https://doi.org/10.1097/PAS.0000000000001351
- Second-line chemotherapy in advanced biliary cancers: A retrospective, multicenter analysis of outcomes
Cancer 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31454426
BACKGROUND: Although gemcitabine plus platinum chemotherapy is the established first-line regimen for advanced biliary cancer (ABC), there is no standard second-line therapy. This study evaluated current practice and outcomes for second-line chemotherapy in patients with ABC across 3 US academic medical centers. METHODS: Institutional registries were reviewed to identify patients who had received second-line chemotherapy for ABC from April 2010 to March 2015 along with their demographics, diagnoses and staging, treatment histories, and clinical outcomes. Overall survival from the initiation of second-line chemotherapy (OS2) was estimated with Kaplan-Meier methods. RESULTS: This study identified 198 patients with cholangiocarcinoma (intrahepatic [61.1%] or extrahepatic [14.1%]) or gallbladder carcinoma (24.8%); 52% received at least 3 lines of systemic chemotherapy. The median OS2 was 11 months (95% confidence interval [CI], 8.8-13.1 months). The median OS2 for patients with intrahepatic cholangiocarcinoma was 13.4 months (95% CI, 10.7-17.8 months), which was longer than that for patients with extrahepatic cholangiocarcinoma (6.8 months; 95% CI, 5-10.6 months) or gallbladder carcinoma (9.4 months; 95% CI, 7.2-12.3 months; P = .018). The median time to second-line treatment failure was 2.2 months (95% CI, 1.8-2.7 months), and it was similar across tumor locations (P = .60). CONCLUSIONS: In this large cohort of patients with ABC treated across 3 academic medical centers after the failure of first-line chemotherapy, the time to treatment failure on standard therapies was short, although the median OS2 was longer than has been reported previously, and more than half of the patients received additional lines of treatment. This multicenter collaboration represents the largest cohort studied to date of second-line chemotherapy for ABC and provides a contemporary benchmark for future clinical trials.
doi: https://doi.org/10.1002/cncr.32463
- Emphysematous Cholecystitis
The New England journal of medicine 2019 Aug;381(8):e14
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31433924
doi: https://doi.org/10.1056/NEJMicm1814551
- An Uncommon Case of Double-Hit Mantle Cell Lymphoma That Demonstrates a Transformation Process
American journal of clinical pathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31433838
OBJECTIVES: Mantle cell lymphoma (MCL) is a mature B-cell lymphoma characterized by CCND1/IGH rearrangement. We reported a case of MCL harboring both CCND1/IGH and MYC/IGH rearrangements that also presented with an aggressive clinical course. METHODS: Biopsy specimens were evaluated by morphological staining, immunohistochemistry, flow cytometry, conventional cytogenetics, fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS). RESULTS: Morphological and immunohistochemical staining of gallbladder samples demonstrated blastoid variant MCL. However, in the bone marrow sample, FISH indicated rearrangements in CCND1/IGH and MYC/IGH. Flow cytometry identified two groups of malignant lymphocytes. We sorted these two groups of cells. NGS then revealed that both cell types carried CCND1/IGH rearrangements and TP53 mutations. Furthermore, the CD19+/CD10+ cells carried additional MYC/IGH rearrangement and NOTCH2 mutation. CONCLUSIONS: The rearrangement of MYC and a mutation in NOTCH2 probably induced the transformation of MCL cells in this patient. This uncommon double-hit MCL case clearly demonstrates a transformation process.
doi: https://doi.org/10.1093/ajcp/aqz133
- Efficacy and Safety of Eluxadoline in Patients With Irritable Bowel Syndrome With Diarrhea Who Report Inadequate Symptom Control With Loperamide: RELIEF Phase 4 Study
The American journal of gastroenterology 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31356229
OBJECTIVES: Irritable bowel syndrome with diarrhea (IBS-D) is a functional gastrointestinal disorder with limited effective treatment options. We evaluated the efficacy and safety of eluxadoline in patients with IBS-D who reported inadequate symptom control with prior loperamide. METHODS: Three hundred forty-six adults with IBS-D (Rome III criteria) were randomly assigned to placebo or eluxadoline 100 mg twice daily for 12 weeks. Patients recorded daily IBS-D symptoms, including worst abdominal pain (WAP) and stool consistency (through Bristol Stool Scale). The primary endpoint was proportion of composite responders, defined as patients who met daily composite response criteria (≥40% WAP improvement and <5 Bristol Stool Scale score) for at least 50% of treatment days, and recorded ≥60 days of diary entries over the 12-week period. RESULTS: Over 12 weeks, a significantly greater proportion of eluxadoline patients achieved the primary composite responder endpoint compared to placebo (22.7% vs 10.3%, P = 0.002), and component endpoints of improvements in stool consistency (27.9% vs 16.7%, P = 0.01) and WAP (43.6% vs 31.0%, P = 0.02). Additionally, a greater proportion of eluxadoline patients met the composite responder endpoint assessed at monthly intervals compared to placebo (weeks 1-4: 14.0% vs 6.9%, P = 0.03; weeks 5-8: 26.7% vs 14.9%, P = 0.006; weeks 9-12: 30.8% vs 16.7%, P = 0.002). Rates of adverse events were comparable in both groups (37.4% vs 35.3%); no treatment-related serious adverse event, cases of sphincter of Oddi spasm, or pancreatitis were reported. DISCUSSION: Eluxadoline appears safe and effective for treating IBS-D symptoms in patients with an intact gallbladder reporting inadequate relief with prior loperamide use.
doi: https://doi.org/10.14309/ajg.0000000000000327
- [Tumor-suspected focal lesion on the renal hilus]
Der Pathologe 2019 Sep;40(5):546-547
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31240450
Mucosal structures of a non-neoplastic organ can result in a pitfall diagnosis of adenocarcinoma in the case of a wrong correlation with other organs, in this case caused by an adherent gallbladder to the hilar structures of the right kidney. Clinical and radiological data are absolutely crucial for a correct classification.
doi: https://doi.org/10.1007/s00292-019-0621-4
- Colorectal metastasis to the gallbladder mimicking a primary gallbladder malignancy: histopathological and molecular characteristics
Histopathology 2019 Sep;75(3):394-404
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31044440
AIMS: Outcomes of colorectal cancer (CRC) treatment and survival have steadily improved during the past decades, accompanied by an increased risk of developing second primary tumours and metastatic tumours at unusual sites. Metastatic CRC can show mucosal colonisation, thereby mimicking a second primary tumour. This potential confusion could lead to incorrect diagnosis and consequently inadequate treatment of the patient. The aim of this study was to differentiate between metastatic CRC and a second primary (gallbladder cancer, GBC) using a combination of standard histopathology and molecular techniques. METHODS AND RESULTS: Ten consecutive patients with both CRC and GBC were identified in our region using the Dutch National Pathology Archive (PALGA). Two patients served as negative controls. Histology of GBC was reviewed by nine pathologists. A combination of immunohistochemistry, microsatellite analysis, genomewide DNA copy number analysis and targeted somatic mutation analysis was used to aid in differential diagnosis. In two patients, CRC and GBC were clonally related, as confirmed by somatic mutation analysis. For one case, this was confirmed by genomewide DNA copy number analysis. However, in both cases, pathologists initially considered the GBC as a second primary tumour. CONCLUSIONS: Metastatic CRC displaying mucosal colonisation is often misinterpreted as a second primary tumour. A combination of traditional histopathology and molecular techniques improves this interpretation, and lowers the risk of inadequate treatment.
doi: https://doi.org/10.1111/his.13892
- IL-33 overexpression in gallbladder cancers associated with pancreatobiliary maljunction
Histopathology 2019 Sep;75(3):365-375
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30882917
AIMS: To investigate whether genetic or inflammatory pro-oncogenic factors are relevant to the increased risk of gallbladder cancers in patients with pancreaticobiliary maljunction (PBM). METHODS AND RESULTS: Mutations in KRAS exon 2 were examined by a highly sensitive, droplet digital PCR platform using surgically resected specimens of PBM-associated (n = 31) and non-associated gallbladder cancers (n = 49). The tissue expression of IL-6 and IL-33, which are suspected to promote biliary carcinogenesis, was analysed by quantitative real-time PCR and in-situ hybridisation. The incidence of KRAS mutations was similarly low in PBM-associated (five of 32 cases; 16%) and non-associated cancers (four of 49 cases; 8%) (P = 0.272). The tissue expression of IL-33 mRNA, but not IL-6 mRNA, was significantly higher in PBM-associated gallbladder cancers than in gallbladder cancers without PBM (P = 0.004). A similar degree of IL-33 overexpression was also observed in the background non-cancerous mucosa in cases of PBM-associated gallbladder cancers, and was significantly greater than that in PBM cases with cholecystitis alone (P < 0.001). The results of in-situ hybridisation indicated that the source of IL-33 production in PBM-associated carcinomas was the endothelium, cancer cells and non-neoplastic biliary epithelium. In a combined PBM-associated and non-associated cohort, IL-33 overexpression in gallbladder cancers correlated with less aggressive features (e.g. a lower pT stage and longer overall survival), similar to recently reported findings on large-duct cholangiocarcinomas. CONCLUSIONS: KRAS mutations do not appear to be associated with a high risk of malignancy in PBM, while IL-33 overexpression may provide a pro-oncogenic microenvironment in the gallbladder mucosa of patients with PBM.
doi: https://doi.org/10.1111/his.13863
- Expression of fatty-acid-binding protein 5 in intrahepatic and extrahepatic cholangiocarcinoma: the possibility of different energy metabolisms in anatomical location
Medical molecular morphology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31432248
The biliary tract cancer (BTC) covers a range of carcinomas, including intrahepatic cholangiocarcinoma (ICC), cholangiolocellular carcinoma (CoCC), perihilar cholangiocarcinoma (perihilar CC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancer (GBC), defined according to the anatomical location. These adenocarcinomas mostly comprise biliary epithelial cell-derived malignant cells. In addition to anatomical differences, there are morphological and biological differences in BTC starting from embryonic development of the tissues extending to physiological differences. Fatty acid-binding proteins (FABPs) are closely associated with the energy metabolism. Using surgical specimens from 74 BTCs, we performed immunohistochemistry for FABP5 and its associated molecules, including peroxisome proliferator-activated receptor γ (PPARγ), PPARγ coactivator 1 (PGC-1), and estrogen-related receptor α (ERRα). We found that the expression patterns of small BTCs (ICC and CoCC) considerably differed from those of large BTCs (perihilar CC, ECC, and GBC). Expression of FABP5 and PGC-1 in large BTCs was high compared with those of small BTCs, but no difference in the expression of PPARγ and ERRα was observed. FABP5 appears to play a role in malignant progression in large BTCs. Small and large BTCs possess different energy metabolism systems owing to their different anatomical locations and course of carcinogenesis, although all BTCs originate from biliary epithelial cells.
doi: https://doi.org/10.1007/s00795-019-00230-9
- Detection of NRG1 Gene Fusions in Solid Tumors
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Aug;25(16):4966-4972
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30988082
PURPOSE: NRG1 gene fusions are rare but potentially actionable oncogenic drivers that are present in some solid tumors. Details regarding the incidence of these gene rearrangements are lacking. Here, we assessed the incidence of NRG1 fusions across multiple tumor types and described fusion partners. EXPERIMENTAL DESIGN: Tumor specimens submitted for molecular profiling at a Clinical Laboratory Improvement Amendments (CLIA)-certified genomics laboratory and that underwent fusion testing by anchored multiplex PCR for targeted RNA sequencing were retrospectively identified. The overall and tumor-specific incidence was noted, as was the specific fusion partner. RESULTS: Out of 21,858 tumor specimens profiled from September 2015 to December 2018, 41 cases (0.2%) harbored an NRG1 fusion. Multiple fusion partners were identified. Fusion events were seen across tumor types. The greatest incidence was in non-small cell lung cancer (NSCLC, 25), though this represented only 0.3% of NSCLC cases tested. Other tumor types harboring an NRG1 fusion included gallbladder cancer, renal cell carcinoma, bladder cancer, ovarian cancer, pancreatic cancer, breast cancer, neuroendocrine tumor, sarcoma, and colorectal cancer. CONCLUSIONS: NRG1 fusions can be detected at a low incidence across multiple tumor types with significant heterogeneity in fusion partner.See related commentary by Dimou and Camidge, p. 4865.
doi: https://doi.org/10.1158/1078-0432.CCR-19-0160
- Transpapillary Endoscopic Removal of Gallbladder Stones Through a Fully Covered Metallic Stent
The American journal of gastroenterology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31403962
doi: https://doi.org/10.14309/ajg.0000000000000367
- A 12-year trend analysis of the incidence of gastrointestinal cancers in East Azerbaijan: last updated results of an ongoing population-based cancer registry
BMC cancer 2019 Aug;19(1):782
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31391032
BACKGROUND: The most recent results of Global Cancer Statistics indicated that gastrointestinal cancers, including gastric, colorectal, esophageal, and liver cancers, are among the most commonly diagnosed cancers worldwide. Previous reports from cancer registries in East Azerbaijan have shown that there is a high incidence of gastrointestinal cancer in this region, so we performed a trend analysis to determine the pattern of change over the last decade. METHODS: In total, 12 years of cancer registry data were collected from different sources in East Azerbaijan, and a data quality check was performed to ensure clean data. Using the 2000 World Health Organization standard population, we then generated age-standardized incidence rates (ASRs) for different cancers, and for each year from 1383 to 1394 of the Persian calendar (i.e., 19 March 2004 to 20 March 2015). Annual percent changes (APCs) and Average annual percent changes (AAPCs) in the ASRs for esophageal, gastric, small intestine, colorectal, anal, liver, gallbladder, and pancreatic cancers were calculated using Joinpoint Software (Version 4.5.0.1, June 2017). RESULTS: An increase in most types of cancer was observed during the study period. The ASR for colorectal cancer increased from 2.9 to 13.6 per 100,000 women (APC, 9.7%) and from 2.2 to 17.8 per 100,000 men (APC, 10.2%). The ASR for gastric cancer showed a slight increasing trend from 10.5 to 13.5 per 100,000 women (APC, 1.3%) and from 3.1 to 29.9 per 100,000 men (APC, 3.2%). However, trend analysis showed a decreasing pattern for the ASR of esophageal cancer in both genders (APC,- 3%), with APCs of - 1.1% in females and - 0.4% in males. CONCLUSIONS: The latest results of the East Azerbaijan Population-Based Cancer Registry indicate that gastrointestinal cancers remain common, with significant increasing trends in their ASRs. Improved screening and early detection are needed in this region.
doi: https://doi.org/10.1186/s12885-019-6008-3
- Classification of the cystic duct patterns and endoscopic transpapillary cannulation of the gallbladder to prevent post-ERCP cholecystitis
BMC gastroenterology 2019 Aug;19(1):139
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31382888
BACKGROUND: Endoscopic transpapillary cannulation of the gallbladder is useful but challenging. This study aimed to investigate cystic duct anatomy patterns, which may guide cystic duct cannulation. METHODS: A total of 226 patients who underwent endoscopic transpapillary cannulation of the gallbladder were analyzed retrospectively. RESULTS: According to the cystic duct take-off, 226 cystic duct patterns were divided into 3 patterns: Type I (193, 85.4%), located on the right and angled up; Type II (7, 3.1%), located on the right and angled down; and Type III (26, 11.5%), located on the left and angled up. Type I was further divided into three subtypes: Line type, S type (S1, not surrounding the common bile duct; S2, surrounding the common bile duct), and α type (α1, forward α; α2, reverse α). Types I and III cystic ducts were easier to be cannulated with a higher success rate (85.1 and 86.4%, respectively) compared with Type II cystic duct (75%) despite no statistically significant difference. The reasons for the failure of gallbladder cannulation included invisible cyst duct take-off, severe cyst duct stenosis, impacted stones in cyst duct or neck of the gallbladder, sharply angled cyst duct, and markedly dilated cyst duct with the tortuous valves of Heister. CONCLUSION: Classification of cystic duct patterns was helpful in guiding endoscopic transpapillary gallbladder cannulation.
doi: https://doi.org/10.1186/s12876-019-1053-6
- Acute Recurrent and Chronic Pancreatitis as Initial Manifestations of Cystic Fibrosis and Cystic Fibrosis Transmembrane Conductance Regulator-Related Disorders
Pancreas 2019 Aug;48(7):888-893
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268981
OBJECTIVES: Recurrent pancreatitis is considered a rare manifestation of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction; this case series highlights that pancreatitis can be a presenting symptoms of cystic fibrosis (CF) or a CFTR-related disorder (CFTR-RD). METHODS: Retrospective review of patients younger than 30 years diagnosed as having acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP) and subsequently diagnosed as having CF or CFTR-RD. RESULTS: Among 18 patients, median time from diagnosis of ARP/CP to diagnosis of CF was 0.4 years (range, 0-33 years). Eight were classified as having CF by elevated sweat chloride testing (SCT). Five had intermediate SCT (30-59 mmol/L) with 2 pathogenic mutations. Five had CFTR-RD with intermediate SCT and 0 to 1 pathogenic mutations. Eight patients (44%) had exocrine pancreatic insufficiency, and pancreatic fluid collections were more common in this group. Based on the CFTR mutation, 6 patients were eligible for CFTR potentiator therapy, although none received it during the study period. Nine of the 18 had ≥1 other likely CF manifestations, including sinusitis (33%), nasal polyps (11%), pneumonia (22%), and gallbladder disease (22%). CONCLUSIONS: Cystic fibrosis or CFTR-RD can present as ARP/CP. Complete diagnostic testing for CFTR-RD in patients with ARP/CP will broaden treatment options and help to identify comorbid illness.
doi: https://doi.org/10.1097/MPA.0000000000001350
- Epithelial Inclusions in Gallbladder May Mimic Parasite Infection
American journal of clinical pathology 2019 Aug;152(3):399-402
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31189015
doi: https://doi.org/10.1093/ajcp/aqz054
- Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: a non-randomised, multicentre, open-label, phase 1 study
The lancet. Gastroenterology & hepatology 2019 Aug;4(8):611-621
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31109808
BACKGROUND: This study aimed to assess the safety and tolerability of the immune checkpoint inhibitor nivolumab, as monotherapy or combined with chemotherapy, in Japanese patients with biliary tract cancer. METHODS: This multicentre, open-label, phase 1 trial was done at four cancer centres in Japan. Eligible patients were aged 20-79 years, had biliary tract adenocarcinoma (intrahepatic bile duct cancer, extrahepatic bile duct cancer, gallbladder cancer, or ampullary cancer), Eastern Cooperative Oncology Group performance status 0 or 1, adequate hepatic, renal, and haematological function, and tumour tissue samples for PD-L1 expression analysis. Patients with unresectable or recurrent biliary tract cancer that was refractory or intolerant to gemcitabine-based treatment regimens received nivolumab monotherapy (240 mg every 2 weeks [monotherapy cohort]). Chemotherapy-naive patients with unresectable or recurrent biliary tract cancer received nivolumab (240 mg every 2 weeks) and cisplatin (25 mg/m2) plus gemcitabine (1000 mg/m2) chemotherapy (combined therapy cohort). The primary objective was to assess tolerability and safety. The primary objective was assessed in the safety population of all patients who had received at least one dose of nivolumab. This study is registered with www.clinicaltrials.jp, number JapicCTI-153098, and follow-up is ongoing. FINDINGS: 30 patients were enrolled into each cohort between Jan 13, 2016, and April 19, 2017. Data cutoff was Aug 31, 2017. In the monotherapy cohort, the most frequently reported treatment-related adverse events were decreased appetite (five [17%]), malaise (four [13%]), and pruritus (four [13%]). Grade 3-4 treatment-related adverse events were reported by three (10%) patients (rash, maculopapular rash, and amylase increase) and treatment-related serious adverse events were reported by one (3%) patient (pleurisy). In the combined therapy cohort, the most frequently reported treatment-related adverse events were neutrophil count decrease (any grade 25 [83%]; grade 3-4 in 23 [77%] patients) and platelet count decrease (any grade 25 [83%] of 30; grade 3-4 in 15 [50%] patients). Six (20%) patients reported 11 treatment-related serious adverse events (platelet count decrease [three patients], febrile neutropenia [two patients], neutrophil count decrease, anaemia, anaphylactic reaction, decreased appetite, pyrexia, and myocarditis [one patient each]). In the monotherapy cohort, median overall survival was 5·2 months (90% CI 4·5-8·7), median progression-free survival was 1·4 months (90% CI 1·4-1·4), and one of 30 patients had an objective response. In the combined therapy cohort, median overall survival was 15·4 months (90% CI 11·8-not estimable), median progression-free survival was 4·2 months (90% CI 2·8-5·6), and 11 of 30 patients had an objective response. INTERPRETATION: Nivolumab had a manageable safety profile and signs of clinical activity in patients with unresectable or recurrent biliary tract cancer. This initial assessment of nivolumab for the treatment of advanced biliary tract cancer provides supportive evidence for future larger randomised studies of nivolumab in this difficult to treat cancer. FUNDING: Ono Pharmaceutical Co Ltd and Bristol-Myers Squibb Inc.
doi: https://doi.org/10.1016/S2468-1253(19)30086-X
- Gallbladder Papilloma in a Child Unmasking Metachromatic Leukodystrophy: A Case Report With Review of Literature
Fetal and pediatric pathology 2019 Aug;38(4):345-351
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30912695
Background: Metachromatic leukodystrophy (MLD) is a lipid storage disease characterized the accumulation of sulfatides in different viscera including the gallbladder. Case report: A 2-year-old girl had upper right quadrant lesion that was preoperatively thought to be a biliary cystadenoma. Histologically, the gallbladder lesion was a tubulo-villous papilloma with multiple foci of papillary mucosal hyperplasia. Many storage histiocytes containing metachromatic granules, characteristic of MLD, were present in the tips of the papillae. MLD was later confirmed by enzyme studies. Conclusion: Gallbladder papilloma can be the presenting feature of MLD.
doi: https://doi.org/10.1080/15513815.2019.1588442
- Incidental Hepatic Tissue Obtained via Routine Cholecystectomy
International journal of surgical pathology 2019 Aug;27(5):499-505
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30520351
Background. The hepatic tissue that may occupy specimens from routine cholecystectomies has yet to be studied. Our objectives were to determine the prevalence of hepatic tissue obtained at routine cholecystectomy, to determine whether such hepatic tissue can histologically withstand technical artifacts commonly associated with cholecystectomy, and to determine whether examining such hepatic tissue has diagnostic utility. Materials and Methods. We retrospectively reviewed 50 specimens from routine cholecystectomies that were performed by surgeons who lacked knowledge of our study. All 50 specimens were grossed according to standard protocol, with only limited, nontargeted sampling of the rough nonperitonealized margin, and were received without fixative. Results. Twelve specimens (24.0%) contained hepatic tissue. The hepatic tissue measured up to 44.5-mm long and 1.8-mm wide and contained up to 11 complete portal tracts. Hepatic tissue in 3 specimens satisfied criteria for adequacy established for core biopsies based on number of portal tracts or size. Despite cautery and delayed fixation, all hepatic tissue had surprisingly well-preserved histology. Pathologic findings included nonalcoholic fatty liver disease, von Meyenburg complex, chronic cholestasis, and senescence. Conclusions. The hepatic tissue that accompanies specimens from routine cholecystectomies may be relatively common, can be large, is well preserved, and can harbor diagnostically useful information.
doi: https://doi.org/10.1177/1066896918817374
- Rilpivirine attenuates liver fibrosis through selective STAT1-mediated apoptosis in hepatic stellate cells
Gut 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31530714
OBJECTIVE: Liver fibrosis constitutes a major health problem worldwide due to its rapidly increasing prevalence and the lack of specific and effective treatments. Growing evidence suggests that signalling through cytokine-activated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways regulates liver fibrosis and regeneration. Rilpivirine (RPV) is a widely used anti-HIV drug not reported to produce hepatotoxicity. We aimed to describe the potential hepatoprotective effects of RPV in different models of chronic liver injury, focusing on JAK-STAT signalling regulation. DESIGN: The effects of RPV on hepatic steatosis, inflammation and fibrogenesis were studied in a nutritional mouse model of non-alcoholic fatty liver disease, carbon tetrachloride-induced fibrosis and bile duct ligation-induced fibrosis. Primary human hepatic stellate cells (hHSC) and human cell lines LX-2 and Hep3B were used to investigate the underlying molecular mechanisms. RESULTS: RPV exerted a clear anti-inflammatory and antifibrotic effect in all the in vivo models of liver injury employed, and enhanced STAT3-dependent proliferation in hepatocytes and apoptosis in HSC through selective STAT1 activation. These results were reproduced in vitro; RPV undermined STAT3 activation and triggered STAT1-mediated pathways and apoptosis in HSC. Interestingly, this selective pro-apoptotic effect completely disappeared when STAT1 was silenced. Conditioned medium experiments showed that HSC apoptosis activated STAT3 in hepatocytes in an interleukin-6-dependent mechanism. CONCLUSION: RPV ameliorates liver fibrosis through selective STAT1-dependent induction of apoptosis in HSC, which exert paracrinal effects in hepatocytes, thus promoting liver regeneration. RPV’s actions may represent an effective strategy to treat chronic liver diseases of different aetiologies and help identify novel therapeutic targets.
doi: https://doi.org/10.1136/gutjnl-2019-318372
- Bile duct involvement by hepatocellular carcinoma: A rare occurrence and poor prognostic indicator in bile duct brushing samples
Cancer cytopathology 2019 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31518056
BACKGROUND: Hepatocellular carcinoma (HCC) rarely involves the biliary tree and may be inadvertently sampled on bile duct brushings (BDBs). METHODS: The pathology archives of 5 institutions were searched for BDBs with HCC involvement. RESULTS: A total of 17 BDBs from 14 patients were obtained. There was a male:female ratio of 6:1; the median age of the patients was 59.5 years (range, 22-80 years). The median hepatic tumor size was 6.2 cm (range, 2.2-13.0 cm). HCC risk factors included viral hepatitis (5 patients), cirrhosis (5 patients), hemochromatosis (1 patient), and alcoholic steatohepatitis (1 patient). Jaundice with elevated bilirubin, liver enzymes, and α-fetoprotein was common. Endoscopic retrograde cholangiopancreatography demonstrated bile duct dilatation, polypoid intraductal masses (5 samples), clots/debris (2 samples), or strictures (4 samples). All BDBs had single and clustered large cells with naked atypical nuclei, granular cytoplasm, high nuclear/cytoplasmic ratios, and nuclei with prominent macronucleoli. Less common findings included clear/microvesicular cytoplasm (35%), papillae (29%), and anisonucleosis (35%). Classic HCC features (widened trabeculae [35%], endothelial wrapping [24%], multinucleation [24%], and cytoplasmic bile pigment [35%]) were uncommon. A total of 11 BDBs were diagnosed as malignant (10 with HCC and 1 with cholangiocarcinoma), 2 were diagnosed as atypical, and 1 BDB was diagnosed as negative; approximately two-thirds were found to have polysomy on fluorescence in situ hybridization. Approximately 71% of patients died of disease at a median of 3.5 months. CONCLUSIONS: HCC may extend into the intrahepatic and/or extrahepatic biliary tree, causing masses and/or strictures that may be sampled on BDB. Although cytologically malignant, the classic features of HCC are uncommon, which can cause misdiagnosis. Cytopathologists should be mindful of this differential when evaluating BDBs, particularly when concomitant liver masses and/or HCC risk factors are present. Because of the associated high mortality and rapid rate of death, its presence should be conveyed clearly in pathology reports.
doi: https://doi.org/10.1002/cncy.22185
- Second-line chemotherapy in advanced biliary cancers: A retrospective, multicenter analysis of outcomes
Cancer 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31454426
BACKGROUND: Although gemcitabine plus platinum chemotherapy is the established first-line regimen for advanced biliary cancer (ABC), there is no standard second-line therapy. This study evaluated current practice and outcomes for second-line chemotherapy in patients with ABC across 3 US academic medical centers. METHODS: Institutional registries were reviewed to identify patients who had received second-line chemotherapy for ABC from April 2010 to March 2015 along with their demographics, diagnoses and staging, treatment histories, and clinical outcomes. Overall survival from the initiation of second-line chemotherapy (OS2) was estimated with Kaplan-Meier methods. RESULTS: This study identified 198 patients with cholangiocarcinoma (intrahepatic [61.1%] or extrahepatic [14.1%]) or gallbladder carcinoma (24.8%); 52% received at least 3 lines of systemic chemotherapy. The median OS2 was 11 months (95% confidence interval [CI], 8.8-13.1 months). The median OS2 for patients with intrahepatic cholangiocarcinoma was 13.4 months (95% CI, 10.7-17.8 months), which was longer than that for patients with extrahepatic cholangiocarcinoma (6.8 months; 95% CI, 5-10.6 months) or gallbladder carcinoma (9.4 months; 95% CI, 7.2-12.3 months; P = .018). The median time to second-line treatment failure was 2.2 months (95% CI, 1.8-2.7 months), and it was similar across tumor locations (P = .60). CONCLUSIONS: In this large cohort of patients with ABC treated across 3 academic medical centers after the failure of first-line chemotherapy, the time to treatment failure on standard therapies was short, although the median OS2 was longer than has been reported previously, and more than half of the patients received additional lines of treatment. This multicenter collaboration represents the largest cohort studied to date of second-line chemotherapy for ABC and provides a contemporary benchmark for future clinical trials.
doi: https://doi.org/10.1002/cncr.32463
- Non Syndromic Paucity of Interlobular Bile Ducts in Children - A Clinicopathological Study
Fetal and pediatric pathology 2019 Aug;():1-17
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31437071
Background: Non syndromic paucity of interlobular bile ducts (NS-PILBD) constitutes a miniscule of infantile cholestasis. Method: Clinical details, investigations, surgical findings, management and outcome of cases of NS-PILBD at liver biopsy were analyzed. Specific histopathological features including bile duct to portal tract ratio were studied. Results: Eighteen cases (1993-2013) are detailed. Clinical presentation and investigations were similar to biliary atresia. Hepatic scintigraphy showed no gut excretion in 13/18 and operative cholangiogram was normal in all. Liver biopsy showed a median Scheuer fibrosis stage of 2, the mean bile duct/portal tract ratio was 0.29. The average age at last follow up of twelve cases was 54.9 months . Ten were asymptomatic and anicteric, the liver function tests had normalized over 3-15 months. Conclusion: Histopathology differentiated NS-PILBD from other causes of infantile cholestasis .The idiopathic form generally had a favorable long term outcome with medical management.
doi: https://doi.org/10.1080/15513815.2019.1652376
- Emphysematous Cholecystitis
The New England journal of medicine 2019 Aug;381(8):e14
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31433924
doi: https://doi.org/10.1056/NEJMicm1814551
- Minimally Invasive Treatment for Severe Acute Pancreatitis With Superior Mesenteric Vein and Common Bile Duct Stenosis: A Case Report and Review of the Literature
Pancreas 2019 Sep;48(8):e61-e63
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31425486
doi: https://doi.org/10.1097/MPA.0000000000001379
- Ursodeoxycholic acid for intrahepatic cholestasis in pregnancy
Lancet (London, England) 2019 09;394(10201):810-812
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31378393
doi: https://doi.org/10.1016/S0140-6736(19)31607-1
- [Tumor-suspected focal lesion on the renal hilus]
Der Pathologe 2019 Sep;40(5):546-547
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31240450
Mucosal structures of a non-neoplastic organ can result in a pitfall diagnosis of adenocarcinoma in the case of a wrong correlation with other organs, in this case caused by an adherent gallbladder to the hilar structures of the right kidney. Clinical and radiological data are absolutely crucial for a correct classification.
doi: https://doi.org/10.1007/s00292-019-0621-4
- Aryl Hydrocarbon Receptor Signaling Prevents Activation of Hepatic Stellate Cells and Liver Fibrogenesis in Mice
Gastroenterology 2019 09;157(3):793-806.e14
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31170413
BACKGROUND & AIMS: The role of aryl hydrocarbon receptor (AhR) in liver fibrosis is controversial because loss and gain of AhR activity both lead to liver fibrosis. The goal of this study was to investigate how the expression of AhR by different liver cell types, hepatic stellate cells (HSCs) in particular, affects liver fibrosis in mice. METHODS: We studied the effects of AhR on primary mouse and human HSCs, measuring their activation and stimulation of fibrogenesis using RNA-sequencing analysis. C57BL/6J mice were given the AhR agonists 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 2-(1’H-indole-3’-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE); were given carbon tetrachloride (CCl4); or underwent bile duct ligation. We also performed studies in mice with disruption of Ahr specifically in HSCs, hepatocytes, or Kupffer cells. Liver tissues were collected from mice and analyzed by histology, immunohistochemistry, and immunoblotting. RESULTS: AhR was expressed at high levels in quiescent HSCs, but the expression decreased with HSC activation. Activation of HSCs from AhR-knockout mice was accelerated compared with HSCs from wild-type mice. In contrast, TCDD or ITE inhibited spontaneous and transforming growth factor β-induced activation of HSCs. Mice with disruption of Ahr in HSCs, but not hepatocytes or Kupffer cells, developed more severe fibrosis after administration of CCl4 or bile duct ligation. C57BL/6J mice given ITE did not develop CCl4-induced liver fibrosis, whereas mice without HSC AhR given ITE did develop CCl4-induced liver fibrosis. In studies of mouse and human HSCs, we found that AhR prevents transforming growth factor β-induced fibrogenesis by disrupting the interaction of Smad3 with β-catenin, which prevents the expression of genes that mediate fibrogenesis. CONCLUSIONS: In studies of human and mouse HSCs, we found that AhR prevents HSC activation and expression of genes required for liver fibrogenesis. Development of nontoxic AhR agonists or strategies to activate AhR signaling in HSCs might be developed to prevent or treat liver fibrosis.
doi: https://doi.org/10.1053/j.gastro.2019.05.066
- The Pathologic and Genetic Characteristics of the Intestinal Subtype of Intraductal Papillary Neoplasms of the Bile Duct
The American journal of surgical pathology 2019 Sep;43(9):1212-1220
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31166202
The present study aimed to identify the pathologic and genetic characteristics of intestinal subtype of intraductal papillary neoplasm of the bile duct (iIPNB) showing columnar cells with pseudostratified, cigar-shaped nuclei, and basophilic or amphophilic cytoplasm with the diffuse immunohistochemical expression of CK20 and/or CDX2. A total of 34 cases of iIPNB were pathologically examined according to their anatomic location (the bile duct) and were then compared with the intestinal subtype of intraductal papillary mucinous neoplasm (iIPMN) of the pancreas (n=22). Mutations of 26 somatic genes were examined in formalin-fixed paraffin-embedded tissue specimens from 21 cases of iIPNB using the TruSight Tumor 26 gene panel and next-generation sequencing. iIPNB cases were divided into intrahepatic (n=6) and extrahepatic (n=28) categories. Intrahepatic IPNBs showed a less-complicated villous-papillary pattern, while extrahepatic IPNBs showed a papillary pattern with tubular and/or villous components and predominant high-grade dysplasia with complicated architectures. MUC5AC was frequently and extensively expressed in intrahepatic iIPNBs and iIPMNs but not in extrahepatic iIPNBs. CD10 was frequently expressed in extrahepatic IPNBs but not in intrahepatic iIPNBs or iIPMN. Genetic mutations of TP53 and PIK3CA, which were infrequent or absent in iIPMNs, were frequently detected in extrahepatic iIPNBs, while KRAS and GNAS, which were commonly observed in iIPMNs, were frequently detected in intrahepatic iIPNBs. Intrahepatic iIPNBs showed villous-papillary growth with features reminiscent of iIPMNs, while extrahepatic iIPNBs showed papillary growth with tubular and/or villous components, complicated histology and variable differences from iIPMNs, suggesting differences in the tumorigenesis of iIPNBs along the biliary tree.
doi: https://doi.org/10.1097/PAS.0000000000001295
- Robotic Left Hepatectomy and Roux-en-Y Hepaticojejunostomy After Bile Duct Injury
Annals of surgical oncology 2019 Sep;26(9):2981-2984
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31147989
BACKGROUND: Bile duct injuries after cholecystectomy remain a major concern because their incidence has not changed through the years despite technical advances. This video presents a robotic left hepatectomy and Roux-en-Y hepaticojejunostomy as a treatment for a complex bile duct injury after laparoscopic cholecystectomy. METHODS: A 52-year-old man underwent laparoscopic cholecystectomy at another institution 8 years previously, which resulted in a bile duct injury. His postoperative period was complicated by jaundice and cholangitis. He was treated with endoscopic retrograde cholangiopancreatography and multiple endoprostheses for 3 years, after which the endoprostheses were removed, and he was sent to the authors’ institution. Computed tomography showed that the left liver had signs of disturbed perfusion and dilation of the left intrahepatic bile duct. The patient was asymptomatic and refused any further attempt at surgical correction of the lesion. He was accompanied for 5 years. Magnetic resonance imaging showed progressive atrophy of the left liver. Finally, 3 months before this writing, he presented with intermittent episodes of cholangitis. A multidisciplinary team decided to perform left hepatectomy with Roux-en-Y hepatojejunostomy via a robotic approach. The left liver was atrophied, and left hepatectomy was performed. Fluorescence imaging was used to identify the right bile duct. At opening of the right bile duct, small stones were found and removed. Antecolic Roux-en-Y hepaticojejunostomy then was performed. RESULTS: The operative time was 335 min. Recovery was uneventful, and the patient was discharged on postoperative day 4. CONCLUSIONS: Robotic repair of bile duct injuries is feasible and safe, even when liver resection is necessary. This video may help oncologic surgeons to perform this complex procedure.
doi: https://doi.org/10.1245/s10434-019-07474-w
- Cytomorphology of intraductal papillary neoplasm of the biliary tract
Diagnostic cytopathology 2019 Sep;47(9):922-926
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31116517
Intraductal papillary neoplasms of the bile duct (IPNBs) are papillary epithelial proliferations with delicate fibrovascular cores within dilated bile ducts. They are thought to be premalignant lesions with potential to progress invasive tumors. To our knowledge, there are no prior descriptions of IPNB cytomorphology. A 58-year-old male presented with painless jaundice and elevated liver function tests was found to have an intraluminal mass within the left hepatic duct. A bile duct brushing diagnosed as “atypical cells present” showed a cellular specimen composed of papillary groups and linear strips of mostly cuboidal/columnar cells with mild atypia and vacuolated cytoplasm. A left hepatic lobectomy including extrahepatic bile ducts showed the mass consisted of papillary cores lined by pancreatobiliary-type epithelium with mild-to-severe atypia, consistent with IPNB with a focus suspicious for invasion. The cytomorphologic features described in the current case suggest intraductal papillary neoplasm but may not be specific since similar features could be seen in other bile duct tumors and even in nonneoplastic conditions such as stent or cholelithiasis. However, it is worthwhile to report papillary hyperplasia with atypia in common bile duct brushings in order to avoid a false-negative diagnosis, especially in the context of a filling defect by images which does not appear to be a stone.
doi: https://doi.org/10.1002/dc.24212
- Acute Methamphetamine-Induced Hepatic and Pancreatic Ischemia
The American journal of forensic medicine and pathology 2019 Sep;40(3):285-288
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31033491
Methamphetamine is a central nervous system stimulant that induces arousal, a positive mood, cardiac stimulation, and an acute improvement in cognitive domains. Its illicit exploitation is rapidly growing in North America. Typically, extended use of the drug induces organ damage via vasoconstriction and subsequent ischemia. This case specifically discusses hepatic and pancreatic pathology resulting from methamphetamine overdose alongside an unusual discovery of globally necrotic von Meyenburg complexes.
doi: https://doi.org/10.1097/PAF.0000000000000486
- Intrahepatic cholestasis: suggested future investigations
Lancet (London, England) 2019 08;394(10198):e17
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31272691
doi: https://doi.org/10.1016/S0140-6736(19)31391-1
- Intrahepatic cholestasis: suggested future investigations - Authors’ reply
Lancet (London, England) 2019 08;394(10198):e18
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31272690
doi: https://doi.org/10.1016/S0140-6736(19)31389-3
- Fragile X mental retardation protein protects against tumour necrosis factor-mediated cell death and liver injury
Gut 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31409605
OBJECTIVE: The Fragile X mental retardation (FMR) syndrome is a frequently inherited intellectual disability caused by decreased or absent expression of the FMR protein (FMRP). Lack of FMRP is associated with neuronal degradation and cognitive dysfunction but its role outside the central nervous system is insufficiently studied. Here, we identify a role of FMRP in liver disease. DESIGN: Mice lacking Fmr1 gene expression were used to study the role of FMRP during tumour necrosis factor (TNF)-induced liver damage in disease model systems. Liver damage and mechanistic studies were performed using real-time PCR, Western Blot, staining of tissue sections and clinical chemistry. RESULTS: Fmr1null mice exhibited increased liver damage during virus-mediated hepatitis following infection with the lymphocytic choriomeningitis virus. Exposure to TNF resulted in severe liver damage due to increased hepatocyte cell death. Consistently, we found increased caspase-8 and caspase-3 activation following TNF stimulation. Furthermore, we demonstrate FMRP to be critically important for regulating key molecules in TNF receptor 1 (TNFR1)-dependent apoptosis and necroptosis including CYLD, c-FLIPS and JNK, which contribute to prolonged RIPK1 expression. Accordingly, the RIPK1 inhibitor Necrostatin-1s could reduce liver cell death and alleviate liver damage in Fmr1null mice following TNF exposure. Consistently, FMRP-deficient mice developed increased pathology during acute cholestasis following bile duct ligation, which coincided with increased hepatic expression of RIPK1, RIPK3 and phosphorylation of MLKL. CONCLUSIONS: We show that FMRP plays a central role in the inhibition of TNF-mediated cell death during infection and liver disease.
doi: https://doi.org/10.1136/gutjnl-2019-318215
- Decompressive laparotomy for abdominal compartment syndrome resulting from severe acute pancreatitis: a case report
BMC gastroenterology 2019 Aug;19(1):141
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31395017
BACKGROUND: Abdominal compartment syndrome (ACS) is associated with mortality in patients with critical illness such as severe acute pancreatitis, but it remains unclear whether decompressive laparotomy for ACS can improve the prognosis of patients. CASE PRESENTATION: A woman in her 60s visited our hospital because of upper abdominal pain. On the basis of her laboratory data and abdominal contrast-enhanced computed tomography findings, acute gallstone pancreatitis was diagnosed. She underwent endoscopic sphincterotomy for the removal of the common bile duct stone. Then, a drainage tube was placed in the bile duct. However, on the 5th hospital day, her intra-abdominal pressure increased to 22 mmHg and renal dysfunction was observed, which led to the diagnosis of ACS. As intensive medical treatments did not improve her ACS, she underwent decompressive laparotomy on the 9th hospital day. Postoperatively, her laboratory data and intravesical pressure improved, and she was discharged from the hospital after abdominal closure, continuous drainage, and antibiotic therapy. CONCLUSION: As the effectiveness of decompressive laparotomy for ACS has not been established, this treatment indication remains controversial. Decompressive laparotomy is considered useful for the management of ACS, if it is performed at an appropriate time, as in the present case.
doi: https://doi.org/10.1186/s12876-019-1059-0
- Classification of the cystic duct patterns and endoscopic transpapillary cannulation of the gallbladder to prevent post-ERCP cholecystitis
BMC gastroenterology 2019 Aug;19(1):139
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31382888
BACKGROUND: Endoscopic transpapillary cannulation of the gallbladder is useful but challenging. This study aimed to investigate cystic duct anatomy patterns, which may guide cystic duct cannulation. METHODS: A total of 226 patients who underwent endoscopic transpapillary cannulation of the gallbladder were analyzed retrospectively. RESULTS: According to the cystic duct take-off, 226 cystic duct patterns were divided into 3 patterns: Type I (193, 85.4%), located on the right and angled up; Type II (7, 3.1%), located on the right and angled down; and Type III (26, 11.5%), located on the left and angled up. Type I was further divided into three subtypes: Line type, S type (S1, not surrounding the common bile duct; S2, surrounding the common bile duct), and α type (α1, forward α; α2, reverse α). Types I and III cystic ducts were easier to be cannulated with a higher success rate (85.1 and 86.4%, respectively) compared with Type II cystic duct (75%) despite no statistically significant difference. The reasons for the failure of gallbladder cannulation included invisible cyst duct take-off, severe cyst duct stenosis, impacted stones in cyst duct or neck of the gallbladder, sharply angled cyst duct, and markedly dilated cyst duct with the tortuous valves of Heister. CONCLUSION: Classification of cystic duct patterns was helpful in guiding endoscopic transpapillary gallbladder cannulation.
doi: https://doi.org/10.1186/s12876-019-1053-6
- Liver biopsy in primary biliary cholangitis: is sinusoidal fibrosis the missing key?
Journal of clinical pathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31371396
AIMS: The role of liver biopsy in primary biliary cholangitis (PBC) is controversial, as is the optimal method of histological assessment. We compared the Ludwig and Ishak systems and three components of the Japanese (Nakanuma) staging system to evaluate their clinical and biochemical correlations and prognostic value. METHODS: We reviewed biopsies from 106 patients with PBC, derived from a previous trial of colchicine therapy with 24-34 years’ follow-up, following which five clinical outcomes were evaluated: hepatic decompensation, cholestatic PBC death/liver transplant, portal hypertensive PBC death, all PBC deaths and overall survival. RESULTS: Ludwig and Ishak stages correlated well with prognostically significant parameters, including serum bilirubin, and both Mayo and Child Scores. Serum aspartate aminotransferase correlated with interface hepatitis (IFH), and alkaline phosphatase with orcein deposition, bile duct (BD) loss and cholestasis. Ludwig correlated with all five clinical outcomes, while Ishak stage was only significantly correlated with two. While sinusoidal fibrosis, orcein deposition, BD loss and cholestasis all predicted hepatic death/transplant, after correction for Mayo Score, the only histological parameters predictive of clinical outcomes were IFH (associated with two) and sinusoidal fibrosis (associated with all five). CONCLUSION: Liver biopsy is required in the diagnosis of around 20% of patients with PBC. The Ludwig system is of more prognostic value than both Ishak and any of the three individual components of the Nakanuma staging system, but the major histological parameter providing independent prognostic value beyond the Mayo Score is sinusoidal fibrosis.
doi: https://doi.org/10.1136/jclinpath-2019-205958
- British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis
Gut 2019 08;68(8):1356-1378
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31154395
These guidelines on the management of primary sclerosing cholangitis (PSC) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included medical representatives from hepatology and gastroenterology groups as well as patient representatives from PSC Support. The guidelines aim to support general physicians, gastroenterologists and surgeons in managing adults with PSC or those presenting with similar cholangiopathies which may mimic PSC, such as IgG4 sclerosing cholangitis. It also acts as a reference for patients with PSC to help them understand their own management. Quality of evidence is presented using the AGREE II format. Guidance is meant to be used as a reference rather than for rigid protocol-based care as we understand that management of patients often requires individual patient-centred considerations.
doi: https://doi.org/10.1136/gutjnl-2018-317993
- Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: a non-randomised, multicentre, open-label, phase 1 study
The lancet. Gastroenterology & hepatology 2019 Aug;4(8):611-621
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31109808
BACKGROUND: This study aimed to assess the safety and tolerability of the immune checkpoint inhibitor nivolumab, as monotherapy or combined with chemotherapy, in Japanese patients with biliary tract cancer. METHODS: This multicentre, open-label, phase 1 trial was done at four cancer centres in Japan. Eligible patients were aged 20-79 years, had biliary tract adenocarcinoma (intrahepatic bile duct cancer, extrahepatic bile duct cancer, gallbladder cancer, or ampullary cancer), Eastern Cooperative Oncology Group performance status 0 or 1, adequate hepatic, renal, and haematological function, and tumour tissue samples for PD-L1 expression analysis. Patients with unresectable or recurrent biliary tract cancer that was refractory or intolerant to gemcitabine-based treatment regimens received nivolumab monotherapy (240 mg every 2 weeks [monotherapy cohort]). Chemotherapy-naive patients with unresectable or recurrent biliary tract cancer received nivolumab (240 mg every 2 weeks) and cisplatin (25 mg/m2) plus gemcitabine (1000 mg/m2) chemotherapy (combined therapy cohort). The primary objective was to assess tolerability and safety. The primary objective was assessed in the safety population of all patients who had received at least one dose of nivolumab. This study is registered with www.clinicaltrials.jp, number JapicCTI-153098, and follow-up is ongoing. FINDINGS: 30 patients were enrolled into each cohort between Jan 13, 2016, and April 19, 2017. Data cutoff was Aug 31, 2017. In the monotherapy cohort, the most frequently reported treatment-related adverse events were decreased appetite (five [17%]), malaise (four [13%]), and pruritus (four [13%]). Grade 3-4 treatment-related adverse events were reported by three (10%) patients (rash, maculopapular rash, and amylase increase) and treatment-related serious adverse events were reported by one (3%) patient (pleurisy). In the combined therapy cohort, the most frequently reported treatment-related adverse events were neutrophil count decrease (any grade 25 [83%]; grade 3-4 in 23 [77%] patients) and platelet count decrease (any grade 25 [83%] of 30; grade 3-4 in 15 [50%] patients). Six (20%) patients reported 11 treatment-related serious adverse events (platelet count decrease [three patients], febrile neutropenia [two patients], neutrophil count decrease, anaemia, anaphylactic reaction, decreased appetite, pyrexia, and myocarditis [one patient each]). In the monotherapy cohort, median overall survival was 5·2 months (90% CI 4·5-8·7), median progression-free survival was 1·4 months (90% CI 1·4-1·4), and one of 30 patients had an objective response. In the combined therapy cohort, median overall survival was 15·4 months (90% CI 11·8-not estimable), median progression-free survival was 4·2 months (90% CI 2·8-5·6), and 11 of 30 patients had an objective response. INTERPRETATION: Nivolumab had a manageable safety profile and signs of clinical activity in patients with unresectable or recurrent biliary tract cancer. This initial assessment of nivolumab for the treatment of advanced biliary tract cancer provides supportive evidence for future larger randomised studies of nivolumab in this difficult to treat cancer. FUNDING: Ono Pharmaceutical Co Ltd and Bristol-Myers Squibb Inc.
doi: https://doi.org/10.1016/S2468-1253(19)30086-X
- Evaluation of histologic changes in the livers of patients with early and late hepatic artery thrombosis
Human pathology 2019 Aug;90():8-13
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31075300
Hepatic artery thrombosis (HAT) following orthotopic liver transplantation (OLT) can cause hepatic parenchymal necrosis and ischemic cholangiopathy. This study investigates additional histologic features that may suggest HAT in post-OLT liver specimens. For 94 liver specimens (explanted allografts and biopsies) from patients with a clinical or pathologic diagnosis of HAT, we recorded length of time between OLT and procedure, categorizing cases into early HAT (;≤30 days since OLT) and late HAT (>30 days since OLT). Common histologic findings in HAT included lobular necrosis (60 cases, 64%), portal inflammation (68 cases, 72%), ductular reaction (73 cases, 78%), lobular cholestasis (70 cases, 74%), and bile-tinged macrophages (40 cases, 43%). Ductular cholestasis was seen in 30 cases (32%); 10 of those patients were clinically septic. Bile in veins was seen in 16 (17%) cases and arteritis in 6 (6%) cases. Findings more common in resection than biopsy specimens included lobular necrosis (P < .0001), hemorrhage (P = .0044), ductular cholestasis (P = .0003), and bile-tinged macrophages (P < .0001). Lobular necrosis was more common in early HAT (P = .0002), and ductular reaction (P = .006) and bile in veins (P = .03) were more common in late HAT. Histologic changes in HAT vary based on specimen type and whether HAT is early or late. In late HAT, biliary injury might occur after a prolonged period of ischemia, with subsequent bile duct necrosis, bile in veins, and remodeling (eg, ductular reaction). Bile in veins is an unusual finding that may occur in HAT, although it can be seen in bile infarcts from other causes.
doi: https://doi.org/10.1016/j.humpath.2019.04.019
- Intraoperative Air Leak Test to Prevent Bile Leak After Right Posterior Sectionectomy with En Bloc Diaphragm Resection for Metastatic Teratoma
Annals of surgical oncology 2019 Aug;26(8):2579
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31065963
BACKGROUND: The intraoperative air cholangiogram, or “air leak test” (ALT), at the time of hepatectomy can significantly reduce the rates of bile leak and symptomatic fluid collection after high-risk procedures.1,2 Because a bile leak in the setting of an en bloc diaphragm resection and mesh reconstruction would be a particularly dreaded complication, this video shows the technique for resection, reconstruction, and ALT. PRESENTATION: The video presents the case of a 29-year-old woman who had metastatic teratoma with an 8 × 7-cm liver metastasis in segment 7 and diaphragm invasion to the level of the right hepatic vein. OPERATION: The authors performed a formal right posterior sectionectomy with en bloc diaphragm resection. The 12 × 8-cm diaphragmatic defect was reconstructed using biologic mesh (Surgimend, Integra LifeSciences, Plainsboro, NJ). An intraoperative ALT (air injection into the cystic duct with finger compression of the distal bile duct) identified several areas of bubbles from biliary radicles on the cut surface of the liver, which were ligated with 4-0 polypropylene. The ALT was repeated until no bubbles remained. Because no evidence of bubbles was observed, no surgical drain was needed. The patient did well postoperatively with no complications. CONCLUSION: In cases of combined liver and diaphragmatic resection, prevention of bile leak, with subsequent contamination of the diaphragm repair and even the thoracic cavity, is particularly vital. An easily replicated intraoperative air leak test can mitigate the risk of bile leak and organ-space infection, as well as associated sequelae on quality of life, return to intended oncologic therapy, and oncologic outcomes.
doi: https://doi.org/10.1245/s10434-019-07410-y
- Microbiota as a cornerstone in the development of primary sclerosing cholangitis: paving the path for translational diagnostic and therapeutic approaches
Gut 2019 08;68(8):1353-1355
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31028154
doi: https://doi.org/10.1136/gutjnl-2019-318487
- Spontaneous Pneumobilia and Hematemesis
Gastroenterology 2019 08;157(2):e8-e9
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30959037
doi: https://doi.org/10.1053/j.gastro.2019.03.053
- Liver Masses
Gastroenterology 2019 08;157(2):e3-e4
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30959031
doi: https://doi.org/10.1053/j.gastro.2019.03.057
- Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis
Gut 2019 08;68(8):1477-1492
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30872395
OBJECTIVE: There is a striking association between human cholestatic liver disease (CLD) and inflammatory bowel disease. However, the functional implications for intestinal microbiota and inflammasome-mediated innate immune response in CLD remain elusive. Here we investigated the functional role of gut-liver crosstalk for CLD in the murine Mdr2 knockout (Mdr2-/-) model resembling human primary sclerosing cholangitis (PSC). DESIGN: Male Mdr2-/-, Mdr2-/- crossed with hepatocyte-specific deletion of caspase-8 (Mdr2-/- /Casp8∆hepa) and wild-type (WT) control mice were housed for 8 or 52 weeks, respectively, to characterise the impact of Mdr2 deletion on liver and gut including bile acid and microbiota profiling. To block caspase activation, a pan-caspase inhibitor (IDN-7314) was administered. Finally, the functional role of Mdr2-/- -associated intestinal dysbiosis was studied by microbiota transfer experiments. RESULTS: Mdr2-/- mice displayed an unfavourable intestinal microbiota signature and pronounced NLRP3 inflammasome activation within the gut-liver axis. Intestinal dysbiosis in Mdr2-/- mice prompted intestinal barrier dysfunction and increased bacterial translocation amplifying the hepatic NLRP3-mediated innate immune response. Transfer of Mdr2-/- microbiota into healthy WT control mice induced significant liver injury in recipient mice, highlighting the causal role of intestinal dysbiosis for disease progression. Strikingly, IDN-7314 dampened inflammasome activation, ameliorated liver injury, reversed serum bile acid profile and cholestasis-associated microbiota signature. CONCLUSIONS: MDR2-associated cholestasis triggers intestinal dysbiosis. In turn, translocation of endotoxin into the portal vein and subsequent NLRP3 inflammasome activation contribute to higher liver injury. This process does not essentially depend on caspase-8 in hepatocytes, but can be blocked by IDN-7314.
doi: https://doi.org/10.1136/gutjnl-2018-316670
- Statin use and reduced risk of biliary tract cancers in the UK Clinical Practice Research Datalink
Gut 2019 08;68(8):1458-1464
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30448774
OBJECTIVE: To evaluate the association between statin use and risk of biliary tract cancers (BTC). DESIGN: This is a nested case-control study conducted in the UK Clinical Practice Research Datalink. We included cases diagnosed with incident primary BTCs, including cancers of the gall bladder, bile duct (ie, both intrahepatic and extrahepatic cholangiocarcinoma), ampulla of Vater and mixed type, between 1990 and 2017. For each case, we selected five controls who did not develop BTCs at the time of case diagnosis, matched by sex, year of birth, calendar time and years of enrolment in the general practice using incidence density sampling. Exposures were defined as two or more prescription records of statins 1 year prior to BTC diagnosis or control selection. ORs and 95% CIs for associations between statins and BTC overall and by subtypes were estimated using conditional logistic regression, adjusted for relevant confounders. RESULTS: We included 3118 BTC cases and 15 519 cancer-free controls. Current statin use versus non-use was associated with a reduced risk of all BTCs combined (adjusted OR=0.88, 95% CI 0.79 to 0.98). The reduced risks were most pronounced among long-term users, as indicated by increasing number of prescriptions (ptrend=0.016) and cumulative dose of statins (ptrend=0.008). The magnitude of association was similar for statin use and risk of individual types of BTCs. The reduced risk of BTCs associated with a record of current statin use versus non-use was more pronounced among persons with diabetes (adjusted OR=0.72, 95% CI 0.57 to 0.91). Among non-diabetics, the adjusted OR for current statin use versus non-use was 0.91 (95% CI 0.81 to 1.03, pheterogeneity=0.007). CONCLUSION: Compared with non-use of statins, current statin use is associated with 12% lower risk of BTCs; no association found with former statin use. If replicated, particularly in countries with a high incidence of BTCs, our findings could pave the way for evaluating the value of statins for BTC chemoprevention.
doi: https://doi.org/10.1136/gutjnl-2018-317504
- Oral vancomycin induces clinical and mucosal remission of colitis in children with primary sclerosing cholangitis-ulcerative colitis
Gut 2019 08;68(8):1533-1535
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30131321
doi: https://doi.org/10.1136/gutjnl-2018-316599
- Clinical value of DPOC for detecting and removing residual common bile duct stones (video)
BMC gastroenterology 2019 Jul;19(1):135
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31349795
BACKGROUND: This study aims to evaluate the efficacy and safety of detecting and removing residual common bile duct stones (CBDS) using direct peroralcholangioscopy (DPOC) after performing endoscopic retrograde cholangiopancreatography (ERCP) for stone retrieval. METHODS: From January 5, 2017 to December 27, 2017, a total of 164 cases of choledocholithiasis were treated by ERCP for stone retrieval. According to the inclusion and exclusion criteria, the remaining 79 cases (39 males; mean age: 63.3 years old, range: 52-79 years old) were enrolled in the present study. The maximum transverse stone diameter was 6-15 mm (12.7 ± 4.2 mm), as determined by ERCP. Furthermore, there were 57 cases of multiple stones (number of stones: two in 41 cases, three in nine cases, and ≥ 4 in seven cases), 13 cases of post-mechanical lithotripsy, and nine cases of broken stones. RESULTS: The overall success rate of DPOC was 94.9% (75/79). Furthermore, 18.7%(14/75) of cases were directly inserted, 72%(54/75) of cases required guide wire assistance, and 9.3%(7/75) of cases were successfully inserted with overtube assistance. The average insertion time was 7-17 min (4.9 ± 2.9 min). Residual stones were detected in 19 cases (25.3%), and all of which were < 5 mm in diameter. Moreover, five cases of formed stones were removed by basket and balloon catheter, while the remaining cases were cleaned after irrigation and suction. There were no serious complications. CONCLUSION: DPOC is safe and effective for both the detection and removal of residual CBDS after conventional ERCP.
doi: https://doi.org/10.1186/s12876-019-1045-6
- Immunoglobulin G4-related hepatobiliary disease
Seminars in diagnostic pathology 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31358425
Immunoglobuline G4-related disease (IgG4-RD) is a systemic disease that can involve virtually any organs including the biliary tract and liver. The biliary tract involvement of IgG4-RD is known as IgG4-sclerosing cholangitis (IgG4-SC) and may or may not present with an inflammatory pseudotumor. Large bile ducts such as extrahepatic, hilar, and perihilar ducts are typically affected and demonstrate marked bile duct wall thickening and develop strictures. Histologically, the involved ducts show transmural dense lymphoplasmacytic infiltrates with storiform fibrosis extending into peribiliary glands and periductal soft tissue. The luminal epithelium is usually preserved. Tissue eosinophilia and obliterative phlebitis are also frequently noted. Liver biopsy findings of IgG4-SC are heterogeneous and rather nonspecific, but two features specific to IgG4-SC have been described: >10 IgG4-positive plasma cell/HPF and small portal-based fibroinflammatory nodules. Secondary changes, due to downstream bile duct obstruction are often appreciated. When considering the differential diagnosis, primary sclerosing cholangitis and cholangiocarcinoma are great clinical and histologic mimics of IgG4-SC. Liver involvement in IgG4-RD has not been well characterized and includes IgG4-hepatopathy and IgG4-related autoimmune hepatitis (AIH). IgG4-hepatopathy is a generic term covering hepatic lesions related to IgG4-RD and /or IgG4-SC. It includes primary liver parenchymal changes inherent to IgG4-RD, liver parenchymal involvement of IgG4-SC, and secondary changes related to IgG4-SC. IgG4-related AIH is characterized by clinical and histologic features of classical AIH but with prominent (>10/HPF) IgG4-positive plasma cells. It is unclear whether this represents a hepatic manifestation of IgG4-RD or a subset of AIH with increased IgG4-positive plasma cells at the present time. Synchronous or metachronous involvement of other organs, offers a clue to make this distinction. IgG4 immunohistochemistry has an important role in diagnosing IgG4-RD. But the diagnosis cannot be made solely based on the number of IgG4-positive plasma cells, and results need to be interpreted with caution as increased IgG4-positive plasma cells can be seen in other inflammatory conditions or even in malignancy.
doi: https://doi.org/10.1053/j.semdp.2019.07.007
- Checkpoint inhibitor-induced liver injury: A novel form of liver disease emerging in the era of cancer immunotherapy
Seminars in diagnostic pathology 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31358424
Liver injury triggered by immune checkpoint inhibitors has been increasingly seen in clinical practice, and the incidence is likely to rise further in the next several years because of expanded indications for cancer immunotherapy. Tissue damage driven by disrupted immune tolerance against self-antigens is called an immune-related adverse event (irAE). irAEs in the liver histologically presents panlobular hepatitis (∼70%), isolated central zonal necrosis (∼20%), primarily granulomatous hepatitis (∼5%), and other minor forms of tissue injury (∼5%). Infiltrating cells are mainly lymphocytes and occasional eosinophils. Unlike classic autoimmune hepatitis (AIH), plasma cell infiltration is not conspicuous. Immunostaining reveals a large number of CD8+ T lymphocytes and a markedly smaller number of CD4+ cells or CD20+ B lymphocytes. The unique CD3+/CD20+ and CD4+/CD8+ ratios shifted in favor of CD8+ cytotoxic T lymphocytes are helpful to discriminate irAEs from other conditions (e.g., AIH, idiosyncratic drug-induced liver injury). Another hepatobiliary manifestation of irAEs is sclerosing cholangitis clinically characterized by elevations of biliary enzymes, diffuse duct wall thickening, and duct dilatation. Lymphocytic infiltration can be observed by endoscopic biopsies from the thick extrahepatic bile ducts, and liver needle biopsies may also show severe lymphocytic cholangitis resembling primary biliary cholangitis. An important differential diagnosis of irAEs is previously asymptomatic or subclinical liver disease unmasked by cancer immunotherapy, which is often challenging and requires close clinicopathological correlations.
doi: https://doi.org/10.1053/j.semdp.2019.07.009
- Development of a Theranostic Convergence Bioradiopharmaceutical for Immuno-PET based Radioimmunotherapy of L1CAM in Cholangiocarcinoma Model
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31337646
PURPOSE: Cholangiocarcinoma (CCA) is a malignancy of bile duct with a poor prognosis. Conventional chemotherapy and radiation therapy are generally ineffective and surgical resection is the only curative treatment for CCA. L1-cell adhesion molecule (L1CAM) has been known as a novel prognostic marker and therapeutic target for CCA. This study aimed to evaluate the feasibility of immuno-positron emission tomography (PET) imaging-based radioimmunotherapy using radiolabeled anti-L1CAM antibody in CCA xenograft model. EXPERIMENTAL DESIGN: We prepared a theranostic convergence bioradiopharmaceutical using chimeric anti-L1CAM antibody (cA10-A3) conjugated with 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelator and labeled with 64Cu or 177Lu and evaluated the immuno-PET or SPECT/CT imaging and biodistribution with 64Cu-/177Lu-cA10-A3 in various CCA xenograft models. Therapeutic efficacy and response monitoring were performed by 177Lu-cA10-A3 and 18F-FDG-PET, respectively, and immunohistochemistry was done by TUNEL and Ki-67. RESULTS: Radiolabeled cA10-A3 antibodies specifically recognized L1CAM in vitro, clearly visualized CCA tumors in immuno-PET and SPECT/CT imaging, and differentiated the L1CAM expression level in CCA xenograft models. 177Lu-cA10-A3 (12.95 MBq/100 μg) showed statistically significant reduction in tumor volumes (P < 0.05) and decreased glucose metabolism (P < 0.01). IHC analysis revealed 177Lu-cA10-A3 treatment increased TUNEL-positive and decreased Ki-67-positive cells, compared with saline, cA10-A3, or 177Lu-isotype. CONCLUSIONS: Anti-L1CAM immuno-PET imaging using 64Cu-cA10-A3 could be translated into the clinic for characterizing the pharmacokinetics and selecting pertinent patient for radioimmunotherapy. Radioimmunotherapy using 177Lu-cA10-A3 may provide survival benefit in L1CAM expressing CCA tumor. Theranostic convergence bioradiopharmaceutical strategy would be applied as an imaging biomarker based personalized medicine in L1CAM expressing CCA patients.
doi: https://doi.org/10.1158/1078-0432.CCR-19-1157
- Response to the Letter to the Editor “Minimally Invasive Versus Open Distal Pancreatectomy (LEOPARD)”
Annals of surgery 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31425333
doi: https://doi.org/10.1097/SLA.0000000000003541
- A case of high-grade pancreatic intraepithelial neoplasia concomitant with type 1 autoimmune pancreatitis: The process underlying both conditions
Pathology international 2019 Mar;69(3):165-171
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30719801
We report a case of high-grade pancreatic intraepithelial neoplasia (PanIN) concomitant with lymphoplasmacytic sclerosing pancreatitis. The patient was an 82-year-old man in whom narrowing of the main pancreatic duct was detected incidentally by abdominal ultrasonography. Magnetic resonance cholangiopancreatography further revealed abrupt narrowing plus distal dilatation of the duct, from the pancreatic body to the tail. Distal pancreatectomy was performed under a preoperative diagnosis of intraductal papillary-mucinous neoplasm. Macroscopic examination of the surgical specimen showed an ill-demarcated, white-gray area and prominent pancreatic atrophy, while histological analysis detected small (<5 mm in diameter) cystic dilatations of the main pancreatic duct and some branch ducts plus pancreatic atrophy with fibrosis and fatty replacement of acinar cells. We also detected variously sized papillary projections, fused glands, and scattered focal papillary proliferation of columnar ductal epithelium comprising cells with elongated, mildly hyperchromatic nuclei, consistent with high-grade PanIN. In addition, we observed marked lymphoplasmacytic infiltration, periductal storiform fibrosis, and obliterative phlebitis. Immunohistochemical staining revealed abundant immunogloblin G4-positive plasma cells, indicative of type 1 autoimmune pancreatitis (AIP). The coexistence of high-grade PanIN and marked lymphoplasmacytic infiltration, typical of AIP, point to a close association between the former, as a carcinogenic process, and the latter, as an immune response.
https://bmjopengastro.bmj.com/content/6/1/e000274
https://diagnosticpathology.biomedcentral.com/articles/10.1186/s13000-019-0807-3
http://www.ijcep.com/files/ijcep0090309.pdf
- Metastatic Gallbladder Carcinoma in Meningioma: A Case Report
Turkish neurosurgery 2019 7;29(2):297-299
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=28731197
Metastases from tumors to systemic cancers are rare. The most common intracranial recipient tumor is meningioma. Metastasis from gallbladder cancer has been previously reported from only one patient during autopsy. We present a case of a 72-year-old woman who underwent surgery for right frontal skull base meningioma. The tumor was completely removed. Histological specimens showed gallbladder carcinomatous metastasis with diffuse neuroendocrine differentiation in meningothelial meningioma. The Ki-67 proliferation index of the meningioma was 3%. Further, 60% positive immunoreactivity with the progesterone receptor was observed in meningioma cells. In carcinoma cells, diffuse positive immunoreactivity with chromogranin, CDX2, CEA, panCK, cytokeratin 7, and synaptophysin was observed. A combination of molecular, metabolic, immunological, and/or hormonal factors may contribute to the pathogenesis of this lesion. It cannot be ruled out that it is more common than expected.
- Corticotropin secreting pancreatic neuroendocrine tumour, a therapeutic management challenge. A presentation of 2 cases
Endocrinologia, diabetes y nutricion 2019 Mar;66(3):204-206
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30482522
- Pancreatic adenocarcinomas with mature blood vessels have better overall survival
Scientific reports 2019 Feb;9(1):1310
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30718678
Pancreatic ductal adenocarcinoma (PDAC) is known for its hypovascularity. Bevacizumab, an anti-angiogenic drug, added to standard chemotherapy demonstrated no improvement in outcome for PDAC. Therefore, we hypothesized that increased vascularity may be associated with improved outcomes in PDAC possibly due to better delivery of tumor specific immune cells. To test this hypothesis, PDAC patients were classified into either high or low CD31 expression groups utilizing mRNA expression from RNA-sequence data in The Cancer Genome Atlas (TCGA) pancreatic cancer cohort. High expression of CD31, which indicates presence of more vascular endothelial cells, was associated with significantly better OS (p = 0.002). Multivariate analysis demonstrated that residual tumor (R1, 2; p = 0.026) and CD31 low expression (p = 0.007) were the only independent predictors that negatively impacted OS. Vascular stability as well as immune response related pathways were significantly upregulated in the CD31 high expressing tumors. Furthermore, there were higher proportions of anti-cancer immune cells infiltration, including activated memory CD4+ T cells (p = 0.038), CD8+ T cells (p = 0.027), gamma-delta T cells (p < 0.001) as well as naïve B cells (p = 0.006), whereas lower proportions of regulatory T cell fractions (p = 0.009), which induce an immune tolerant microenvironment, in the CD31 high expressing tumors. These findings imply that stable vessels supply anti-cancer immune cells, which are at least partially responsible for better OS in the CD31 high expressing tumors. In conclusion, CD31 high expressing PDACs have better OS, which may be due to stable vessels that supply anti-cancer immune cells.
- S100A8 and S100A9 proteins form part of a paracrine feedback loop between pancreatic cancer cells and monocytes
BMC cancer 2018 Dec;18(1):1255
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30558665
BACKGROUND: The secretion of soluble factors enables communication between tumour cells and the surrounding microenvironment and plays an important role in oncogenesis. Pancreatic ductal adenocarcinoma (PDAC) is characterised by a highly reactive microenvironment, harbouring a variety of cell types, including S100A8/S100A9-expressing monocytes. S100A8/S100A9 proteins regulate the behaviour of cancer cells by inducing pre-metastatic cascades associated with cancer spread. The aim of this study was to examine how S100A8/A9 proteins mediate tumour-stroma crosstalk in PDAC. METHODS: Cytokine profiling of pancreatic cancer cell-derived conditioned media was performed using Bio-Plex Pro 27 Plex Human Cytokine assays. Protein expression and activation of downstream signalling effectors and NF-κB were assessed by western blotting analysis and reporter assays respectively. RESULTS: Stimulation of cultured pancreatic cancer cells with S100A8 and S100A9 increased the secretion of the pro-inflammatory cytokines IL-8, TNF-α, and FGF. S100A8, but not S100A9 induced PDGF secretion. Conversely, pancreatic cancer cell-derived conditioned media and the individual cytokines, TNF-α and TGF-β induced the expression of S100A8 and S100A9 proteins in the HL-60 monocytic cell line and primary human monocytes, while FGF and IL-8 induced the expression of S100A9 only. S100A8 and S100A9 activated MAPK and NF-κB signalling in pancreatic cancer. This was partially mediated via activation of the receptor of advanced glycosylation end-product (RAGE). CONCLUSION: S100A8 and S100A9 proteins induce specific cytokine secretion from PDAC cells, which in turn enhances the expression of S100A8/A9. This paracrine crosstalk could have implications for PDAC invasiveness and metastatic potential.
- Homeodomain-interacting protein kinase 2 suppresses proliferation and aerobic glycolysis via ERK/cMyc axis in pancreatic cancer
Cell proliferation 2019 May;52(3):e12603
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30932257
OBJECTIVES: To investigate the roles of the homeodomain-interacting protein kinase (HIPK) family of proteins in pancreatic cancer prognosis and the possible molecular mechanism. MATERIALS AND METHODS: The expression of HIPK family genes and their roles in pancreatic cancer prognosis were analysed by using The Cancer Genome Atlas (TCGA). The roles of HIPK2 in pancreatic cancer proliferation and glycolysis were tested by overexpression of HIPK2 in pancreatic cancer cells, followed by cell proliferation assay, glucose uptake analysis and Seahorse extracellular flux analysis. The mechanism of action of HIPK2 in pancreatic cancer proliferation and glycolysis was explored by examining its effect on the ERK/cMyc axis. RESULTS: Decreased HIPK2 expression indicated worse prognosis of pancreatic cancer. Overexpression of HIPK2 in pancreatic cancer cells decreased cell proliferation and attenuated aerobic glycolysis, which sustained proliferation of cancer cells. HIPK2 decreased cMyc protein levels and expression of cMyc-targeted glycolytic genes. cMyc was a mediator that regulated HIPK2-induced decrease in aerobic glycolysis. HIPK2 regulated cMyc protein stability via ERK activation, which phosphorylated and controlled cMyc protein stability. CONCLUSIONS: HIPK2 suppressed proliferation of pancreatic cancer in part through inhibiting the ERK/cMyc axis and related aerobic glycolysis.
Techniques, Research Methods, Liquid Biopsy
- Computational modeling of pancreatic cancer patients receiving FOLFIRINOX and gemcitabine-based therapies identifies optimum intervention strategies
PloS one 2019 04;14(4):e0215409
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31026288
Pancreatic ductal adenocarcinoma (PDAC) exhibits a variety of phenotypes with regard to disease progression and treatment response. This variability complicates clinical decision-making despite the improvement of survival due to the recent introduction of FOLFIRINOX (FFX) and nab-paclitaxel. Questions remain as to the timing and sequence of therapies and the role of radiotherapy for unresectable PDAC. Here we developed a computational analysis platform to investigate the dynamics of growth, metastasis and treatment response to FFX, gemcitabine (GEM), and GEM+nab-paclitaxel. Our approach was informed using data of 1,089 patients treated at the Massachusetts General Hospital and validated using an independent cohort from Osaka Medical College. Our framework establishes a logistic growth pattern of PDAC and defines the Local Advancement Index (LAI), which determines the eventual primary tumor size and predicts the number of metastases. We found that a smaller LAI leads to a larger metastatic burden. Furthermore, our analyses ascertain that i) radiotherapy after induction chemotherapy improves survival in cases receiving induction FFX or with larger LAI, ii) neoadjuvant chemotherapy improves survival in cases with resectable PDAC, and iii) temporary cessations of chemotherapies do not impact overall survival, which supports the feasibility of treatment holidays for patients with FFX-associated adverse effects. Our findings inform clinical decision-making for PDAC patients and allow for the rational design of clinical strategies using FFX, GEM, GEM+nab-paclitaxel, neoadjuvant chemotherapy, and radiation.
- Analysis of BRCAness with multiplex ligation-dependent probe amplification using formalin-fixed and paraffin-embedded pancreatic ductal adenocarcinoma tissue obtained via endoscopic ultrasound-guided fine-needle aspiration biopsy
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Apr;19(3):419-423
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30819577
BACKGROUND/OBJECTIVES: A breakthrough in chemotherapy for pancreatic ductal adenocarcinoma (PDAC) may be achieved using precision medicine, which involves identifying cases that are highly likely to respond to a certain treatment and then performing that treatment. BRCAness has been receiving attention as a novel predictor of anticancer drug sensitivity in PDAC, making the screening of BRCAness paramount. METHODS: We conducted the first-ever examination of the feasibility of analyzing BRCAness using multiplex ligation-dependent probe amplification (MLPA). Formalin-fixed paraffin-embedded (FFPE) tissue samples obtained via endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) from 20 patients with the highest pancreatic carcinoma cell counts in tissue samples out of 40 consecutive PDAC patients who underwent EUS-FNAB at our hospital were analyzed by MLPA for BRCAness. RESULTS: We were able to accurately analyze BRCAness in 75% of the 20 cases of PDAC using FFPE tissue obtained by EUS-FNAB. BRCAness was observed in one of the 20 cases. CONCLUSIONS: In PDAC, analyzing BRCAness by MLPA using FFPE tissue obtained by EUS-FNAB offers the remarkable benefit of yielding results in a short period of time and at a low cost. In addition, this method of BRCAness analysis may prove to be a feasible and effective approach for performing precision medicine.
https://www.annualreviews.org/doi/abs/10.1146/annurev-cancerbio-030518-055702
- Integrating next-generation sequencing to endoscopic retrograde cholangiopancreatography (ERCP)-obtained biliary specimens improves the detection and management of patients with malignant bile duct strictures
Gut 2019 Apr;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30971436
OBJECTIVE: Despite improvements in imaging, serum CA19-9 and pathological evaluation, differentiating between benign and malignant bile duct strictures remains a diagnostic conundrum. Recent developments in next-generation sequencing (NGS) have opened new opportunities for early detection and management of cancers but, to date, have not been rigorously applied to biliary specimens. DESIGN: We prospectively evaluated a 28-gene NGS panel (BiliSeq) using endoscopic retrograde cholangiopancreatography-obtained biliary specimens from patients with bile duct strictures. The diagnostic performance of serum CA19-9, pathological evaluation and BiliSeq was assessed on 252 patients (57 trainings and 195 validations) with 346 biliary specimens. RESULTS: The sensitivity and specificity of BiliSeq for malignant strictures was 73% and 100%, respectively. In comparison, an elevated serum CA19-9 and pathological evaluation had sensitivities of 76% and 48%, and specificities of 69% and 99%, respectively. The combination of BiliSeq and pathological evaluation increased the sensitivity to 83% and maintained a specificity of 99%. BiliSeq improved the sensitivity of pathological evaluation for malignancy from 35% to 77% for biliary brushings and from 52% to 83% for biliary biopsies. Among patients with primary sclerosing cholangitis (PSC), BiliSeq had an 83% sensitivity as compared with pathological evaluation with an 8% sensitivity. Therapeutically relevant genomic alterations were identified in 20 (8%) patients. Two patients with ERBB2-amplified cholangiocarcinoma received a trastuzumab-based regimen and had measurable clinicoradiographic response. CONCLUSIONS: The combination of BiliSeq and pathological evaluation of biliary specimens increased the detection of malignant strictures, particularly in patients with PSC. Additionally, BiliSeq identified alterations that may stratify patients for specific anticancer therapies.
https://link.springer.com/article/10.1007/s11605-019-04203-2
https://www.ncbi.nlm.nih.gov/pubmed/30850740
https://www.nature.com/articles/d41586-019-00710-z
- Why is pancreatic cancer so deadly? The pathologist’s view
The Journal of pathology 2019 Jun;248(2):131-141
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30838636
The remarkable aggressiveness of pancreatic cancer has never been fully explained. Although clearly multifactorial, we postulate that venous invasion, a finding seen in most pancreatic cancers but not in most cancers of other organs, may be a significant, underappreciated contributor to the aggressiveness of this disease. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
- Metabolic Alterations as a Signpost to Early Pancreatic Cancer
Gastroenterology 2019 05;156(6):1560-1563
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30926350
https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0650-0
- Early Detection of Pancreatic Cancer: Opportunities and Challenges
Gastroenterology 2019 05;156(7):2024-2040
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30721664
Most patients with pancreatic ductal adenocarcinoma (PDAC) present with symptomatic, surgically unresectable disease. Although the goal of early detection of PDAC is laudable and likely to result in significant improvement in overall survival, the relatively low prevalence of PDAC renders general population screening infeasible. The challenges of early detection include identification of at-risk individuals in the general population who would benefit from longitudinal surveillance programs and appropriate biomarker and imaging-based modalities used for PDAC surveillance in such cohorts. In recent years, various subgroups at higher-than-average risk for PDAC have been identified, including those with familial risk due to germline mutations, a history of pancreatitis, patients with mucinous pancreatic cysts, and elderly patients with new-onset diabetes. The last 2 categories are discussed at length in terms of the opportunities and challenges they present for PDAC early detection. We also discuss current and emerging imaging modalities that are critical to identifying early, potentially curable PDAC in high-risk cohorts on surveillance.
https://ascopubs.org/doi/abs/10.1200/JCO.18.01512
- Epidemiology, Tumor Characteristics, and Survival in Patients With Primary Pancreatic Lymphoma: A Large Population-based Study Using the SEER Database
American journal of clinical oncology 2019 May;42(5):454-458
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30950860
INTRODUCTION: Primary pancreatic lymphoma (PPL) is an extranodal manifestation of non-Hodgkin lymphoma originating in the pancreas, which constitutes <1% of all pancreatic neoplasms. Because of the rarity of the disease, most data on PPL are derived from case reports and small case series. To provide better insight into the epidemiology, treatment, and outcomes of these patients, we conducted an analysis of patients with PPL from the Surveillance, Epidemiology and End Results (SEER) database, which is presented in this study. METHODS: Patients with PPL were identified using the International Classification of Disease for Oncology, third edition histology codes for lymphoma (9590/3-9734/3), with pancreas (C25.0-C25.9) listed as the primary disease site. We collected data on patient demographics, year of diagnosis, primary tumor site, histology, first line of treatment received, and survival until death or last follow-up for the period 1973-2014. RESULTS: Overall, 835 patients were included. The median (range) age of the study population was 67 (2 to 98) years. The median (95% confidence interval) overall survival for the cohort was 53 (37 to 73) months. On univariable analyses, age, stage, and use of chemotherapy were statistically associated with improved overall survival. Besides these factors, white race was associated with improved cause-specific survival on multivariable analysis. CONCLUSIONS: This large population-based series describes PPL in detail. Younger age, white race, early stage, and initial treatment with chemotherapy are associated with improved survival in patients with PPL.
- Increasing negative lymph node count is independently associated with improved long-term survival in resectable perihilar cholangiocarcinomas
Medicine 2019 Apr;98(15):e14943
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30985643
To evaluate the prognostic value of numbers of negative lymph nodes (NLNs) for patients with perihilar cholangiocarcinomas.The surveillance, epidemiology, and end results database was used to screen for patients with perihilar cholangiocarcinomas. Kaplan-Meier and Cox regression analyses were used for statistical evaluations. Subsequently, propensity score matching (PSM) was performed to confirm the results.A total of 938 patients with perihilar cholangiocarcinomas met the inclusion criteria. The cut-off number for the grouping of patients with different numbers of NLNs was 17. Both the univariate and multivariate survival analyses demonstrated that there was a significant improvement in terms of cancer-specific survival for patients with >17 NLNs, compared with patients with ≤17 NLNs. Then, the above results were confirmed via a PSM procedure. Additionally, the independent prognostic value of NLNs was evaluated in subgroup univariate and multivariate analyses of patients with stage I or stage II tumors.The numbers of NLNs were evaluated and determined to be important independent prognostic factors for the cancer-specific survival of patients with perihilar cholangiocarcinomas.
- The impact of surgery in metastatic pancreatic neuroendocrine tumors: a competing risk analysis
Endocrine connections 2019 Mar;8(3):239-251
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30726772
Aim The role of surgery in the treatment of metastatic pancreatic neuroendocrine tumors (PNETs) was controversial. The objectives of this study were to illustrate the impact of surgery in improving the prognosis of patients with metastatic PNETs and build nomograms to predict overall survival (OS) and cancer-specific survival (CSS) based on a large population-based cohort. Methods Patients diagnosed with metastatic PNETs between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database were retrospectively collected. Nomograms for estimating OS and CSS were established based on Cox regression model and Fine and Grey’s model. The precision of the nomograms was evaluated and compared using concordance index (C-index) and the area under receiver operating characteristic (ROC) curve (AUC). Results The study cohort included 1966 patients with metastatic PNETs. It was shown that the surgery provided survival benefit for all groups of patients with metastatic PNETs. In the whole study cohort, 1-, 2- and 3-year OS and CSS were 51.5, 37.1 and 29.4% and 53.0, 38.9 and 31.1%, respectively. The established nomograms were well calibrated, and had good discriminative ability, with C-indexes of 0.773 for OS prediction and 0.774 for CSS prediction. Conclusions Patients with metastatic PNETs could benefit from surgery when the surgery tolerance was acceptable. The established nomograms could stratify patients who were categorized as tumor-node-metastasis (TNM) IV stage into groups with diverse prognoses, showing better discrimination and calibration of the established nomograms, compared with 8th TNM stage system in predicting OS and CSS for patients with metastatic PNETs.
- Pancreatic islet cell tumors in adolescents and young adults
Journal of pediatric surgery 2019 Mar;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30954230
BACKGROUND: Pancreatic islet cell tumors are rare in adolescents, and most studies published to date focus on older patients. We utilized a national database to describe the histology and clinical pattern of pancreatic islet cell tumors in adolescent and young adult (AYA) patients, and to compare AYAs to older adults. We hypothesized that AYAs with pancreatic islet cell tumors would have better overall survival. METHODS: The National Cancer Data Base (NCDB, 1998-2012) was queried for AYA patients (15-39 years) with a pancreatic islet cell tumor diagnosis. Demographics, tumor characteristics, treatment modalities, and outcomes were abstracted and compared to adults (≥40 years). RESULTS: 383 patients (56.4% female, 65% non-Hispanic Whites) were identified, with a median age of 27 (IQR 16-34) years. Islet cell carcinoma was the most common histology. Of patients with known stage of disease, 49% presented with early stage (I or II). Seventy percent of patients underwent surgical resection, including local excision 44%, Whipple procedure 37.5%, or total pancreatectomy 19%. Chemotherapy was utilized in 27% and radiotherapy in 7%. All-cause mortality was 36%. AYA patients underwent more extensive resections (p = 0.001) and had lower mortality rates (p < 0.001), with no differences in tumor stage or use of adjuvant therapies, when compared to adults. CONCLUSIONS: AYA patients with pancreatic islet cell tumors had comparable utilization of adjuvant therapies but underwent more extensive resections and demonstrated a higher overall survival rate than adult counterparts. Further investigation into approaches to earlier diagnosis and tailoring of multimodality therapy of these neoplasms in the AYA population is needed. LEVELS OF EVIDENCE: Prognostic Study, Level II - retrospective study.
- Non-functional pancreatic neuroendocrine tumours: emerging trends in incidence and mortality
BMC cancer 2019 Apr;19(1):334
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30961556
BACKGROUND: Our aim was to determine the epidemiology and recent changes in the trends of non-functional pancreatic neuroendocrine tumours (NF-pNETs) at the population level. In addition, we explored the risk factors that are associated with survival duration. METHODS: Cases were identified form the Surveillance, Epidemiology, and End Results (SEER) Programme database from 2000 to 2014. Data on incidence and incidence-based (IB) mortality for NF-pNET were obtained from this database. Secular trends in age-adjusted incidence and IB mortality were determined by using the Joinpoint Regression program. Data analyses were performed using chi-square tests, Kaplan-Meier curves and Cox proportional hazards regression. RESULTS: Overall, 4766 patients diagnosed with NF-pNET with a median age of 59 years were identified through our descriptive criteria. Caucasian patients accounted for the majority of the study population, and the proportion of patients with distant disease significantly decreased during our study period. Overall, there was an increase in incidence and IB mortality for NF-pNET; however, the rate of increase decreased during the recent years. In addition, the incidence trends of NF-pNET located in the pancreatic head significantly increased, and rates fo increase in IB mortality for NF-pNET in the pancreatic tail decreased in recent years. Additionally, the 1-, 5-, and 10-year survival rates were 79.0, 51.8, 38.1%, respectively. Furthermore, patient age, tumour grade, stage at diagnosis, tumour size, tumour site and resection were associated with mortality. CONCLUSION: Despite increases in incidence and IB mortality, the rate of change in IB mortality for NF-pNET has decreased in recent years. Survival duration displayed a secular increase during the overall period, and the prognosis and survival duration of patients were closely related to the time of diagnosis, age of the patients and size and location of the tumour. Appropriate treatment adjustments based on tumour stage may thus facilitate improvements in patient outcomes.
- Incidence and comparative outcomes of periampullary cancer: A population-based analysis demonstrating improved outcomes and increased use of adjuvant therapy from 2004 to 2012
Journal of surgical oncology 2019 03;119(3):303-317
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30561818
BACKGROUND AND OBJECTIVES: Periampullary adenocarcinoma (PAC) is stratified anatomically: ampullary adenocarcinoma (AA), distal cholangiocarcinoma (DCC), duodenal adenocarcinoma (DA), and pancreatic ductal adenocarcinoma (PDAC). We aimed to determine differences in incidence, prognosis, and treatment in stage-matched PAC patients in a longitudinal study. METHODS: PAC patients were identified in The National Cancer Database from 2004 to 2012. Clinicopathological variables were compared between subtypes. Covariate-adjusted treatment use and OS were compared. RESULTS: The 116 705 patients with PAC were identified: 1320 (9%) AA, 3732 (3%) DCC, 7142 (6%) DA, and 95 511 (82%) PDAC. DA, DCC, and PDAC were associated with worse survival compared with AA (hazard ratio [HR], 1.10; 95% CI, 1.1-1.1; HR, 1.50; 95% CI, 1.4-1.6, and HR, 1.90; 95% CI, 1.8-1.9). Among resected patients, DA was associated with improved survival compared with AA (HR, 0.70; 95% CI, 0.67-0.75); DCC and PDAC were associated with worse survival (HR, 1.41; 95% CI, 1.31-1.53 and HR, 2.041; 95% CI, 1.07-2.12). Resected AA, PDAC, and DA, but not DCC, demonstrated significantly improved survival over the studied period. While all patients had increased adjuvant therapy (AT) receipt over time (P < 0.001), only patients with PDAC had increased neoadjuvant therapy (NAT) receipt ( P < 0.001). CONCLUSION: Resected PDAC, AA, and DA were associated with clinically significant improved survival over time, mirroring a concurrent associated increased receipt of AT.
https://www.sciencedirect.com/science/article/pii/S0748798319304937
https://link.springer.com/article/10.1007%2Fs00268-019-04913-3
https://link.springer.com/article/10.1007/s11605-019-04252-7
https://www.sciencedirect.com/science/article/pii/S149938721930116X
https://onlinelibrary.wiley.com/doi/abs/10.1002/dc.24212
https://www.annualreviews.org/doi/abs/10.1146/annurev-physiol-020518-114515?journalCode=physiol
https://www.annualreviews.org/doi/abs/10.1146/annurev-physiol-020518-114515
https://www.sciencedirect.com/science/article/abs/pii/S0046817719300899
https://www.gastrojournal.org/article/S0016-5085(19)40525-8/pdf
https://www.sciencedirect.com/science/article/pii/S0016508519408627
https://onlinelibrary.wiley.com/doi/abs/10.1111/his.13897
https://jeccr.biomedcentral.com/articles/10.1186/s13046-019-1209-9
https://link.springer.com/article/10.1245/s10434-019-07390-z
https://journals.sagepub.com/doi/abs/10.1177/0300891619839461
https://www.surgeryjournal.co.uk/article/S0263-9319(19)30070-5/abstract
- Complete Regression of Advanced Pancreatic Ductal Adenocarcinomas upon Combined Inhibition of EGFR and C-RAF
Cancer cell 2019 Apr;35(4):573-587.e6
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30975481
Five-year survival for pancreatic ductal adenocarcinoma (PDAC) patients remains below 7% due to the lack of effective treatments. Here, we report that combined ablation of EGFR and c-RAF expression results in complete regression of a significant percentage of PDAC tumors driven by Kras/Trp53 mutations in genetically engineered mice. Moreover, systemic elimination of these targets induces toxicities that are well tolerated. Response to this targeted therapy correlates with transcriptional profiles that resemble those observed in human PDACs. Finally, inhibition of EGFR and c-RAF expression effectively blocked tumor progression in nine independent patient-derived xenografts carrying KRAS and TP53 mutations. These results open the door to the development of targeted therapies for PDAC patients.
- Pancreatic Ductal Adenocarcinoma Derived From an Intraductal Papillary Neoplasm With Synchronous Incidental Glucagonoma: A Case Report and Literature Review
Pancreas 2019 04;48(4):e24-e26
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30973467
- Pancreatic Cancer Early Detection and Interception in an Atypical Case of Peutz-Jeghers Syndrome
Pancreas 2019 04;48(4):e29-e30
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30973470
- Factors Predicting Response, Perioperative Outcomes, and Survival Following Total Neoadjuvant Therapy for Borderline/Locally Advanced Pancreatic Cancer
Annals of surgery 2019 Apr;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30946090
MINI: Total neoadjuvant therapy, or systemic induction chemotherapy followed by chemoradiation, is an optimal preoperative sequencing strategy for patients with borderline resectable or locally advanced pancreatic adenocarcinoma. This strategy allows high rate of negative margins despite low frequency of radiologic downstaging with survival dependent on chemotherapy duration and response factors that are potentially modifiable by alteration in initial systemic therapy decisions.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 OBJECTIVE:: To identify predictive factors associated with operative morbidity, mortality, and survival outcomes in patients with borderline resectable (BR) or locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) undergoing total neoadjuvant therapy (TNT). The optimal preoperative treatment sequencing for BR/LA PDA is unknown. TNT, or systemic chemotherapy followed by chemoradiation (CRT), addresses both occult metastases and positive margin risks and thus is a potentially optimal strategy; however, factors predictive of perioperative and survival outcomes are currently undefined. We reviewed our experience in BR/LA patients undergoing resection from 2010 to 2017 following TNT assessing operative morbidity, mortality, and survival in order to define outcome predictors and response endpoints. One hundred ninety-four patients underwent resection after TNT, including 123 (63%) BR and 71 (37%) LA PDAC. FOLFIRINOX or gemcitabine along with nab-paclitaxel were used in 165 (85%) and 65 (34%) patients, with 36 (19%) requiring chemotherapeutic switch before long-course CRT and subsequent resection. Radiologic anatomical downstaging was uncommon (28%). En bloc venous and/or arterial resection was required in 125 (65%) patients with 94% of patients achieving R0 margins. The 90-day major morbidity and mortality was 36% and 6.7%, respectively. Excluding operative mortalities, the median, 1-year, 2-year, and 3-year recurrence-free survival (RFS) [overall survival (OS)] rates were 23.5 (58.8) months, 65 (96)%, 48 (78)%, and 32 (62)%, respectively. Radiologic downstaging, vascular resection, and chemotherapy regimen/switch were not associated with survival. Only 3 factors independently associated with prolonged survival, including extended duration (≥6 cycles) chemotherapy, optimal post-chemotherapy CA19-9 response, and major pathologic response. Patients achieving all 3 factors had superior survival outcomes with a survival detriment for each failing factor. In a subset of patients with interval metabolic (PET) imaging after initial chemotherapy, complete metabolic response highly correlated with major pathologic response. Our TNT experience in resected BR/LA PDAC revealed high negative margin rates despite low radiologic downstaging. Extended duration chemotherapy with associated biochemical and pathologic responses highly predicted postoperative survival. Potential modifications of initial chemotherapy treatment include extending cycle duration to normalize CA19-9 or achieve complete metabolic response, or consideration of chemotherapeutic switch in order to achieve these factors may improve survival before moving forward with CRT and subsequent resection.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0.
- The Role of Exosomes in Pancreatic Cancer Microenvironment
Bulletin of mathematical biology 2018 05;80(5):1111-1133
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=28382422
Exosomes are nanovesicles shed by cells as a means of communication with other cells. Exosomes contain mRNAs, microRNAs (miRs) and functional proteins. In the present paper, we develop a mathematical model of tumor-immune interaction by means of exosomes shed by pancreatic cancer cells and dendritic cells. Cancer cells’ exosomes contain miRs that promote their proliferation and that inhibit immune response by dendritic cells, and by CD4+ and CD8+ T cells. Dendritic cells release exosomes with proteins that induce apoptosis of cancer cells and that block regulatory T cells. Simulations of the model show how the size of the pancreatic cancer can be determined by measurement of specific miRs (miR-21 and miR-203 in the case of pancreatic cancer), suggesting these miRs as biomarkers for cancer.
- Pancreatitis and Pancreatic Cancer
Gastroenterology 2019 05;156(7):1937-1940
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30940522
- Autophagy Inhibition in Pancreatic Adenocarcinoma
Clinical colorectal cancer 2018 03;17(1):25-31
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29223362
Although some progress has been made in recent years with the development of more effective chemotherapy regimens, new treatment approaches are needed to improve outcomes for patients with pancreatic adenocarcinoma. The cellular process of autophagy, a cell survival mechanism that allows cancer cells to survive the hazardous conditions of the tumor microenvironment and treatment, has emerged as a viable target in pancreatic cancer. We review the mechanism of autophagy, its role in pancreatic carcinogenesis, the preclinical and clinical evidence supporting targeting autophagy in patients with pancreatic adenocarcinoma, and areas of future investigation that hold promise for improving this treatment approach.
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-019-1304-y
http://www.cancercellresearch.org/PDF/20192108.pdf
- Brain Metastases in Pancreatic Ductal Adenocarcinoma: Assessment of Molecular Genotype-Phenotype Features-An Entity With an Increasing Incidence?
Clinical colorectal cancer 2018 06;17(2):e315-e321
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29496399
PURPOSE: To assess clinical characteristics of patients with metastatic pancreas ductal adenocarcinoma (PDAC) and brain metastases (BM), and to assess somatic and germ-line molecular profiles where performed. PATIENTS AND METHODS: Patients with PDAC and BM between January 1990 and January 2016 were identified. Molecular characteristics of somatic and germ-line testing where performed in the subset of patients who had provided informed consent. Somatic alterations were assessed by either MSK-IMPACT testing (>340 key cancer genes) or Sequenom testing (8-gene panel). Overall survival was calculated from date of diagnosis to either date of last follow-up or death. Survival after BM was calculated from date of diagnosis of BM by radiology or pathology to either date of last follow-up or death. RESULTS: From a total of 5824 patients with PDAC identified from January 2000 to January 2016, twenty-five patients (0.4%) had BM. Median age at PDAC diagnosis was 58 years. Median time to the development of BM from initial PDAC diagnosis was 17 months (range, 0-79 months). Median overall survival after BM diagnosis was 1.5 months (range, 1-31 months). Overall survival for patients who had craniotomy (n = 4) was 11 months (range, 1-31 months), with 2 long-term survivors at 21 and 31 months, respectively. Four patients had leptomeningeal disease. Six of 25 patients had germ-line testing, and 3 had BRCA mutations (2 BRCA1 and 1 BRCA2). Somatic profiling identified KRAS mutations in 100% (4 G12D, 2 G12V, and 1 Q61K). CONCLUSION: BM from PDAC is a rare event. We identified a speculative association of germ-line BRCA1/2 alterations with BM in PDAC, which requires corroboration. Survival after BM development is poor; prolonged survival occurred in selected patients via a multidisciplinary approach.
- Endoscopic Ultrasound Guidance in Diagnosing a Rare Case of Lung Adenocarcinoma Metastatic to the Pancreas
Pancreas 2019 04;48(4):e30-e31
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30973471
https://link.springer.com/article/10.1007/s00592-019-01335-4
https://jeccr.biomedcentral.com/articles/10.1186/s13046-019-1153-8
Mouse Models Shed Light on the SLIT/ROBO Pathway in Pancreatic Development and Cancer.
https://www.ncbi.nlm.nih.gov/pubmed/30898261
Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer.
https://www.ncbi.nlm.nih.gov/pubmed/30635425
Tumor microenvironment participates in metastasis of pancreatic cancer.
https://www.ncbi.nlm.nih.gov/pubmed/30060755
Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance
https://ascopubs.org/doi/full/10.1200/JCO.18.01512
Stromal fibronectin expression in patients with resected pancreatic ductal adenocarcinoma.
https://www.ncbi.nlm.nih.gov/pubmed/30736807
Clinical assessment of the GNAS mutation status in patients with intraductal papillary mucinous neoplasm of the pancreas
https://link.springer.com/article/10.1007/s00595-019-01797-7
Adipophilin expression is an indicator of poor prognosis in patients with pancreatic ductal adenocarcinoma: An immunohistochemical analysis.
https://www.ncbi.nlm.nih.gov/pubmed/30879968
Enrichment of oral microbiota in early cystic precursors to invasive pancreatic cancer
https://gut.bmj.com/content/early/2019/03/13/gutjnl-2018-317458.abstract
Abstracts from USCAP 2019: Pancreas, Gallbladder, Ampulla, and Extra-Hepatic Biliary Tree (1667-1734).
https://www.ncbi.nlm.nih.gov/pubmed/30886253
Abstracts from USCAP 2019: Pancreas, Gallbladder, Ampulla, and Extra-Hepatic Biliary Tree (1667-1734).
https://www.ncbi.nlm.nih.gov/pubmed/30886283
Stromal protein βig-h3 reprogrammes tumour microenvironment in pancreatic cancer.
https://www.ncbi.nlm.nih.gov/pubmed/30415234
https://www.ncbi.nlm.nih.gov/pubmed/30890543
FOLFIRINOX Adjuvant Therapy for Pancreatic Cancer. Reply. https://www.ncbi.nlm.nih.gov/pubmed/30893544
FOLFIRINOX Adjuvant Therapy for Pancreatic Cancer. https://www.ncbi.nlm.nih.gov/pubmed/30893543
https://www.ncbi.nlm.nih.gov/pubmed/30855431
https://www.ncbi.nlm.nih.gov/pubmed/30855430
https://www.sciencedirect.com/science/article/pii/S1424390319300493
https://www.nature.com/articles/s41591-019-0368-8
https://onlinelibrary.wiley.com/doi/abs/10.1111/pin.12778
https://www.gastrojournal.org/article/S0016-5085(19)32505-3/fulltext
https://link.springer.com/article/10.1245/s10434-019-07271-5
https://link.springer.com/article/10.1007/s11605-019-04126-y
https://link.springer.com/article/10.1245/s10434-019-07271-5
https://iris.unito.it/retrieve/handle/2318/1694079/484693/fonc-09-00115.pdf
https://www.sciencedirect.com/science/article/abs/pii/S1365182X19300668
https://link.springer.com/article/10.1186/s40792-019-0590-0
https://onlinelibrary.wiley.com/doi/abs/10.1002/bjs.11111
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379296/
https://wjso.biomedcentral.com/articles/10.1186/s12957-019-1574-z
http://cancerdiscovery.aacrjournals.org/content/9/2/173.abstract
https://www.karger.com/Article/Abstract/497291
https://academic.oup.com/carcin/advance-article-abstract/doi/10.1093/carcin/bgz024/5308868
30348057
- Image-Based Profiling of Patient-Derived Pancreatic Tumor-Stromal Cell Interactions Within a Micropatterned Tumor Model
Technology in cancer research & treatment 2018 01;17():1533033818803632
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30348057
Pancreatic cancer is one of the most aggressive cancers with a 5-year patient survival rate of 8.2% and limited availability of therapeutic agents to target metastatic disease. Pancreatic cancer is characterized by a dense stromal cell population with unknown contribution to the progression or suppression of tumor growth. In this study, we describe a microengineered tumor stromal assay of patient-derived pancreatic cancer cells to study the heterotypic interactions of patient pancreatic cancer cells with different types of stromal fibroblasts under basal and drug-treated conditions. The population dynamics of tumor cells in terms of migration and viability were visualized as a functional end point. Coculture with cancer-associated fibroblasts increased the migration of cancer cells when compared to dermal fibroblasts. Finally, we imaged the response of a bromodomain and extraterminal inhibitor on the viability of pancreatic cancer clusters surrounding by stroma in microengineered tumor stromal assay. We visualized a codynamic reduction in both cancer and stromal cells with bromodomain and extraterminal treatment compared to the dimethyl sulfoxide-treated group. This study demonstrates the ability to engineer tumor-stromal assays with patient-derived cells, study the role of diverse types of stromal cells on cancer progression, and precisely visualize a coculture during the screening of therapeutic compounds.
30742911
- Impact of Immunotherapy after Resection of Pancreatic Cancer
Journal of the American College of Surgeons 2019 Jul;229(1):19-27.e1
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30742911
BACKGROUND: Adjuvant immunotherapy has improved outcomes in patients with advanced melanoma; however, the potential benefit for patients with pancreatic ductal adenocarcinoma (PDAC) remains unknown. The aim of this study was to determine the impact of adjuvant chemotherapy and immunotherapy (CTx-IT) compared with CTx alone on patient survival after resection of PDAC. STUDY DESIGN: Patients who underwent resection of PDAC from 2004 to 2015 were identified from the National Cancer Database. Univariate and multivariate Cox proportional hazards models were used to determine predictors of overall survival (OS) based on the type of adjuvant therapy received. Patients who received adjuvant immunotherapy were compared with those who received adjuvant CTx alone by propensity score matching. RESULTS: Of 21,313 patients who received curative-intent resection for PDAC followed by adjuvant systemic therapy, 269 (1.3%) patients were treated with adjuvant CTx-IT. Propensity score matching resulted in a cohort of 477 patients: (229 CTx only and 248 CTx-IT). The 5-year OS was higher in the CTx-IT group compared with CTx alone (29.2% vs 18.3%; p = 0.0045). On multivariate analysis, the addition of adjuvant immunotherapy was associated was improved overall survival (hazard ratio 0.74; p = 0.007). CONCLUSIONS: The addition of adjuvant immunotherapy to chemotherapy is associated with improved survival compared with chemotherapy alone after curative-intent resection of pancreatic adenocarcinoma. Future research is warranted to match specific immunotherapy agents with susceptible patient populations to improve outcomes for this aggressive disease.
- Biomarker-driven and molecularly targeted therapies for pancreatic adenocarcinoma
Seminars in oncology 2018 06;45(3):107-115
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30391013
Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with few effective treatment options. Our knowledge of molecular alterations in PDAC has significantly grown and helped identify new therapeutic targets. The success of immune checkpoint inhibition in mismatch repair deficient tumors, PARP inhibitors for tumors with DNA repair defects, and targeting hyaluronan with PEGPH20 in patients with high expressing (hyaluronan-high) tumors are examples of promising biomarker-driven therapies. We review the major biological mechanisms in PDAC and discuss current and future directions for molecularly targeted therapies in this disease.
30747828
- Prediction of Recurrence With KRAS Mutational Burden Using Ultrasensitive Digital Polymerase Chain Reaction of Radial Resection Margin of Resected Pancreatic Ductal Adenocarcinoma
Pancreas 2019 03;48(3):400-411
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30747828
OBJECTIVE: Although complete surgical resection is the only curative method for pancreatic cancer, the radial resection margins of pylorus-preserving pancreaticoduodenectomy specimens might be underevaluated. METHODS: KRAS mutation was assessed with droplet digital polymerase chain reaction on cells collected from the radial resection margins of 81 patients, and the results were compared with those of conventional pathologic resection margin (pRM) evaluation. RESULTS: KRAS mutation was detected in 76 patients (94%), and molecular resection margin (mRM) positivity defined by a KRAS mutation rate of 4.19% or greater was observed in 18 patients (22%). Patients with mRM-positive had significantly worse recurrence-free survival (RFS) than those with mRM-negative in entire groups (P = 0.008) and in subgroups without chemotherapy or radiation therapy (all, P < 0.001). When combined pRMs-mRMs were evaluated, patients with combined pRM-mRM-positive (either pRM- or mRM-positive) had significantly worse RFS than those with combined resection margin-negative (both pRM and mRM negative) by univariate (P = 0.002) and multivariate (P = 0.03) analyses. CONCLUSIONS: KRAS mutational analysis with ultrasensitive droplet digital polymerase chain reaction of the radial resection margin in pancreatic cancer patients who underwent pylorus-preserving pancreaticoduodenectomy can provide more accurate information on RFS by using alone or in combination with conventional pRM evaluation, especially in patients without chemotherapy or radiation therapy.
30768986
- The Role of the Microbiome in Immunologic Development and its Implication For Pancreatic Cancer Immunotherapy
Gastroenterology 2019 05;156(7):2097-2115.e2
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30768986
Our understanding of the microbiome and its role in immunity, cancer initiation, and cancer progression has evolved significantly over the past century. The “germ theory of cancer” was first proposed in the early 20th century, and shortly thereafter the bacterium Helicobacter pylori, and later Fusobacterium nucleatum, were implicated in the development of gastric and colorectal cancers, respectively. However, with the development of reliable mouse models and affordable sequencing technologies, the most fascinating aspect of the microbiome-cancer relationship, where microbes undermine cancer immune surveillance and indirectly promote oncogenesis, has only recently been described. In this review, we highlight the essential role of the microbiome in immune system development and maturation. We review how microbe-induced immune activation promotes oncogenesis, focusing particularly on pancreatic carcinogenesis, and show that modulation of the microbiome augments the anti-cancer immune response and enables successful immunotherapy against pancreatic cancer.
30428588
- From Friend to Enemy: Dissecting the Functional Alteration of Immunoregulatory Components during Pancreatic Tumorigenesis
International journal of molecular sciences 2018 Nov;19(11):
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30428588
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a 5-year survival rate of approximately 8%. More than 80% of patients are diagnosed at an unresectable stage due to metastases or local extension. Immune system reactivation in patients by immunotherapy may eliminate tumor cells and is a new strategy for cancer treatment. The anti-CTLA-4 antibody ipilimumab and anti-PD-1 antibodies pembrolizumab and nivolumab have been approved for cancer therapy in different countries. However, the results of immunotherapy on PDAC are unsatisfactory. The low response rate may be due to poor immunogenicity with low tumor mutational burden in pancreatic cancer cells and desmoplasia that prevents the accumulation of immune cells in tumors. The immunosuppressive tumor microenvironment in PDAC is important in tumor progression and treatment resistance. Switching from an immune tolerance to immune activation status is crucial to overcome the inability of self-defense in cancer. Therefore, thoroughly elucidation of the roles of various immune-related factors, tumor microenvironment, and tumor cells in the development of PDAC may provide appropriate direction to target inflammatory pathway activation as a new therapeutic strategy for preventing and treating this cancer.
30747829
- Development and Biological Analysis of a Novel Orthotopic Peritoneal Dissemination Mouse Model Generated Using a Pancreatic Ductal Adenocarcinoma Cell Line
Pancreas 2019 Mar;48(3):315-322
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30747829
OBJECTIVES: Peritoneal dissemination (PD) is an important cause of morbidity and mortality among patients with pancreatic ductal adenocarcinoma (PDAC). We sought to develop and characterized a novel PD mouse model by using a previously established PDAC cell line TCC-Pan2. METHODS: TCC-Pan2 cell line was characterized for growth rate, tumor markers, histology, and somatic mutations. TCC-Pan2 cells were implanted orthotopically to produce PD. TCC-Pan2 cells from these metastatic foci were expanded in vitro and then implanted orthotopically in mice. This PD model was used for comparing the antitumor effect of paclitaxel and NK105. RESULTS: Orthotopically implanted TCC-Pan2 cells caused tumor formation and PD with high frequency in mice. A potent metastatic subline-Pan2M-was obtained. NK105 exerted a stronger antitumor effect than paclitaxel against Pan2M cells harboring a luciferase gene (Pan2MmLuc). Notably, the survival rate on day 80 in the Pan2MmLuc mouse model was 100% for the NK105 group and 0% for the paclitaxel group. CONCLUSION: TCC-Pan2 cell line and Pan2MmLuc PD model can serve as useful tools for monitoring the responses to antineoplastic agents and for studying PDAC biology.
- Incidence and Mortality Rates of Second Pancreatic Cancer Among Survivors of Digestive Cancers: A Nationwide Population-Based Study
Pancreas 2019 03;48(3):412-419
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30768577
OBJECTIVES: We analyzed the incidence and mortality rates of second pancreatic ductal adenocarcinoma (PDAC) among survivors of digestive cancers in South Korea. METHODS: We evaluated data from the Korea National Health Insurance to identify individuals with digestive cancers in 2005 to 2015. The standardized incidence ratios (SIRs) of second PDACs and survival rates were evaluated. RESULTS: Among 772,534 patients with first digestive cancers, 1696 (0.22%) developed second PDACs. The incidence of second PDACs increased until 10 years since the first cancer diagnosis. Patients with biliary tract cancers (BTCs) showed a higher incidence of second PDACs than did those with gastrointestinal cancers or hepatocellular carcinoma. In ages 20 to 49 years, SIRs (95% confidence interval) were higher in survivors of hepatocellular carcinoma (3.08; 1.04-3.08), gastric cancer (3.40; 1.90-3.40), colorectal cancer (5.00; 2.75-5.00), gallbladder cancer (58.52; 11.81-58.52), intrahepatic cholangiocarcinoma (86.99; 1.73-86.99), extrahepatic cholangiocarcinoma (89.41; 27.42-89.41), and ampulla of Vater cancer (156.78; 48.08-156.78). In ages 50 to 64 years, colorectal cancer (1.42; 1.04-1.42), gastric cancer (1.66; 1.29-1.66), and BTCs revealed higher SIRs. In ages more than 65 years, SIR was increased only in BTCs. Second PDACs revealed a more favorable prognosis than first PDACs. CONCLUSIONS: Careful surveillance for second PDACs after curative treatment of BTCs and colorectal cancers should be considered.
30737032
- SNHG14 enhances gemcitabine resistance by sponging miR-101 to stimulate cell autophagy in pancreatic cancer
Biochemical and biophysical research communications 2019 Mar;510(4):508-514
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30737032
BACKGROUND: Due to the poor prognosis and high mortality (over 90%), Pancreas ductal adenocarcinoma (PDAC) is listed as the 7th leading cause of cancer-related death in the world, while gemcitabine sensitivity is key important in PDAC therapy. SNHG14 is thought to be an oncogene in cancer progression. However, the possible role of SNHG14 underlying the progress of the PDAC cell, specifically in gemcitabine resistance remains to be determined. METHODS: We analyzed the PDAC-related data collected from TCGA. PDAC cell line (SW1990) was used as in vitro model. RT-qPCR and western blot were used to detect the autophagy-related gene expression level. MTT and flow cytometry approaches were used to determine cell viability and apoptosis rate. The luciferase reporter assay was used to confirm the direct interaction between SNHG14 and miR-101. The wound healing assay and transwell assay were used to detect the migration and invasion abilities of PDAC cells. RESULTS: The expression of SNHG14 was significantly higher in the PDAC tissues than in the normal tissues, while miR-101 was significantly downregulated in the PDAC tissues. Moreover, the correlation analysis showed that SNHG14 was negatively correlated with miR-101. The in vitro experiments furthermore confirmed their impacts on PDAC cells. Overexpression of SNHG14 and miR-101 inhibitor significantly enhanced cell proliferation, migration, and invasion rate of PDAC cell line. Moreover, SNHG14 knockdown and miR-101 mimics both led to attenuation of gemcitabine resistance-PDAC cell viability and promoted cell apoptosis rate, as well as the reduction of autophagy-related proteins (such as RAB5A and ATG4D). Overexpression of SNHG14 enhanced PDAC cell progression and inhibited cell apoptosis in gemcitabine treatment, as well as the increase of autophagy-related proteins, thus enhanced the chemoresistance of PDAC cells to gemcitabine. CONCLUSIONS: Collectively, we first time revealed that SNHG14 could sponge miR-101 to enhance PDAC cell progression and find the specific axis of SNHG14/miR-101/autophagy underlying the chemoresistance in PDAC cells to gemcitabine, which could promote the progress of PDAC therapy.
30747226
- A 6‑gene risk score system constructed for predicting the clinical prognosis of pancreatic adenocarcinoma patients
Oncology reports 2019 Mar;41(3):1521-1530
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30747226
Pancreatic adenocarcinoma (PAC) is the most common type of pancreatic cancer, which commonly has an unfavorable prognosis. The present study aimed to develop a novel prognostic prediction strategy for PAC patients. mRNA sequencing data of PAC (the training dataset) were extracted from The Cancer Genome Atlas database, and the validation datasets (GSE62452 and GSE79668) were acquired from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) between good and poor prognosis groups were analyzed by limma package, and then prognosis‑associated genes were screened using Cox regression analysis. Subsequently, the risk score system was constructed and confirmed using Kaplan‑Meier (KM) survival analysis. After the survival associated‑clinical factors were screened using Cox regression analysis, they were performed with stratified analysis. Using DAVID tool, the DEGs correlated with risk scores were conducted with enrichment analysis. The results revealed that there were a total of 242 DEGs between the poor and good prognosis groups. Afterwards, a risk score system was constructed based on 6 prognosis‑associated genes (CXCL11, FSTL4, SEZ6L, SPRR1B, SSTR2 and TINAG), which was confirmed in both the training and validation datasets. Cox regression analysis showed that risk score, targeted molecular therapy, and new tumor (the new tumor event days after the initial treatment according to the TCGA database) were significantly related to clinical prognosis. Under the same clinical condition, 6 clinical factors (age, history of chronic pancreatitis, alcohol consumption, radiation therapy, targeted molecular therapy and new tumor (event days) had significant associations with clinical prognosis. Under the same risk condition, only targeted molecular therapy was significantly correlated with clinical prognosis. In conclusion, the 6‑gene risk score system may be a promising strategy for predicting the outcome of PAC patients.
- Emerging Role of Immune Checkpoint Blockade in Pancreatic Cancer
International journal of molecular sciences 2018 Nov;19(11):
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30405053
Immune checkpoint blockade (ICB) with programmed cell death protein-1(PD-1)/programmed death ligand -1(PD-L1) antibodies has revolutionized the management of several cancers, especially non-small cell lung cancer, melanoma, urothelial, and renal cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers associated with high morbidity and mortality. Based on available data, it’s obvious that ICB has limited success in PDACs, which can be explained by the low immunogenicity and immunosuppressive tumor microenvironment of these tumors. In this review article, we focus on PD-L1 expression and microsatellite instability (MSI) in PDAC, and their roles as prognostic and predictive markers. We also discuss data supporting combination therapies to augment cancer immunity cycle. Combining anti-PD-1/PD-L1 agents with other modalities such as vaccines, chemotherapy, and radiation could potentially overcome resistance patterns and increase immune responsiveness in PDAC.
30755305
- Targeting Pancreatic Stellate Cells in Cancer
Trends in cancer 2019 Feb;5(2):128-142
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30755305
Pancreatic stellate cells (PSCs) are the major contributor to the aggressive, metastatic, and resilient nature of pancreatic ductal adenocarcinoma (PDAC), which has a poor prognosis with a 5-year survival rate of 8%. PSCs constitute more than 50% of the tumor stroma in PDAC, where they induce extensive desmoplasia by secreting abundant extracellular matrix (ECM) proteins. In addition, they establish dynamic crosstalk with cancer cells and other stromal cells, which collectively supports tumor progression via various inter- and intracellular pathways. These cellular interactions and associated pathways may reveal novel therapeutic opportunities against this unmet clinical problem. In this review article, we discuss the role of PSCs in inducing tumor progression, their crosstalk with other cells, and therapeutic strategies to target PSCs.
30768573
- Plasma Pancreastatin Predicts the Outcome of Surgical Cytoreduction in Neuroendocrine Tumors of the Small Bowel
Pancreas 2019 03;48(3):356-362
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30768573
OBJECTIVES: Elevated pancreastatin (PST) levels have been shown to be associated with poor prognosis in small bowel neuroendocrine tumors (NETs). We hypothesized that plasma PST levels that remain elevated following surgical cytoreduction portend a poor prognosis in well-differentiated small bowel NETs. METHODS: Patients diagnosed with small bowel NETs who underwent surgical cytoreduction at our institution were identified. Demographics, histopathologic characteristics, and biochemical data were collected. Only patients who had serial preoperative PST (PreopPST) and postoperative PST (PostopPST) levels were included in this study. Patients were sorted into groups by PST level to assess their response to surgical cytoreduction (group 1, PreopPST/PostopPST normal; group 2, PreopPST elevated/PostopPST normal; group 3, PreopPST/PostopPST elevated). Survival rates were calculated from the date of surgery. RESULTS: PreopPST and PostopPST levels were collected from 300 patients. Patients in groups 1 (n = 74) and 2 (n = 81) had a significant survival advantage compared with patients in group 3 (n = 145) (P < 0.0001). Kaplan-Meier 5- and 10-year survival rates were as follows: group 1: 93% and 82%; group 2: 91% and 65%; and group 3: 58% and 34%, respectively. CONCLUSIONS: Serial monitoring of plasma PST is useful in predicting long-term survival following surgical cytoreduction and can be helpful to identify patients who have a poor prognosis.
30747823
- Expression and Clinical Significance of Protein Kinase RNA-Like Endoplasmic Reticulum Kinase and Phosphorylated Eukaryotic Initiation Factor 2α in Pancreatic Ductal Adenocarcinoma
Pancreas 2019 Mar;48(3):323-328
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30747823
OBJECTIVES: Endoplasmic reticulum stress and subsequent phosphorylation of eukaryotic initiation factor 2α (eIF2α) by protein kinase R-like endoplasmic reticulum kinase (PERK) plays an important role in the development and chemoresistance of pancreatic ductal adenocarcinoma (PDAC). However, the expression and significance of phosphorylated eIF2α (p-eIF2α) and PERK in PDAC have not been examined. METHODS: We examined p-eIF2α and PERK expression in 84 PDAC and paired normal pancreas samples by immunohistochemistry and Western blotting and correlated the results with clinicopathologic parameters and survival. RESULTS: Mean PERK H score was 140.8 in PDAC compared with 82.1 in normal pancreas (P < 0.001). High p-eIF2α expression was present in 56% of PDACs versus 7.6% of normal pancreases (P < 0.001). High PERK and p-eIF2α expression correlated with shorter overall survival (P = 0.048 and P = 0.03, respectively). By multivariate analysis, high p-eIF2α (P = 0.01), positive margin (P = 0.002), and lymph node metastasis (P = 0.01) were independent prognosticators for survival. CONCLUSIONS: The expression levels of PERK and p-eIF2α are higher in PDAC than those in normal pancreas. High levels of PERK and p-eIF2α are predictors of shorter survival in PDAC patients, suggesting that PERK and eIF2α could be promising targets in PDAC.
30756314
- Evaluation of the New American Joint Committee on Cancer Staging Manual 8th Edition for Perihilar Cholangiocarcinoma
Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract 2019 Feb;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30756314
BACKGROUND: The aim was to compare the prognostic accuracy of cross-sectional imaging of the 7th and 8th editions of the American Joint Committee on Cancer(AJCC) staging system for perihilar cholangiocarcinoma(PHC). METHODS: All patients with PHC between 2002 and 2014 were included. Imaging at the time of presentation was reassessed and clinical tumor-node-metastasis (cTNM) stage was determined according to the 7th and 8th editions of the AJCC staging system. Comparison of the prognostic accuracy was performed using the concordance index (c-index). RESULTS: A total of 248 PHC patients were included;45 patients(18.1%) underwent a curative-intent resection, whereas 203 patients(81.9%) did not because they were unfit for surgery or were diagnosed with locally advanced or metastatic disease during workup. Prognostic accuracy was comparable between the 7th and 8th editions (c-index 0.57 vs 0.58). For patients who underwent a curative-intent resection, the prognostic accuracy of the 8th edition (0.67) was higher than the 7th (0.65). For patients who did not undergo a curative-intent resection, the prognostic accuracy was poor in both the 7th as the 8th editions (0.54 vs 0.57). CONCLUSION: The 7th and 8th editions of the AJCC staging system for PHC have comparable prognostic accuracy. Prognostic accuracy was particularly poor in unresectable patients.
30747827
- Performance of DAXX Immunohistochemistry as a Screen for DAXX Mutations in Pancreatic Neuroendocrine Tumors
Pancreas 2019 03;48(3):396-399
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30747827
OBJECTIVES: DAXX immunohistochemistry (IHC) is often used as a surrogate for sequencing. We aimed to elucidate the sensitivity of IHC for DAXX mutation. METHODS: All pancreatic neuroendocrine tumors (PanNETs) with DAXX mutations detected by sequencing and a subset of DAXX wild-type PanNETs were analyzed for DAXX expression by IHC. RESULTS: Of 154 PanNETs with MSK-IMPACT testing, 36 (30%) harbored DAXX mutations. DAXX mutations were associated with TSC2 mutations (46% vs 10%, P < 0.0001), tended to co-occur with MEN1 mutations (63% vs 49%, P = 0.11), and tended to be mutually exclusive with ATRX mutations (11% vs 25%, P = 0.053). Of 27 available DAXX mutant PanNETs, 23 lost DAXX expression (85.2%). All 4 DAXX mutants with retained expression harbored DAXX mutations within the SUMO-interacting motif of the last exon. Telomere-specific fluorescence in situ hybridization demonstrated alternative lengthening of telomeres in all 4 cases. Of 20 PanNETs with wild-type DAXX, 19 retained DAXX IHC expression (95%). CONCLUSIONS: The sensitivity and specificity of IHC for DAXX mutation are 85% and 95%, respectively. Last exon DAXX mutant PanNETs often show alternative lengthening of telomeres despite retained DAXX expression, likely due to escape of nonmediated decay.
30768574
- Desmoplasia in Lymph Node Metastasis of Pancreatic Adenocarcinoma Reveals Activation of Cancer-Associated Fibroblasts Pattern and T-helper 2 Immune Cell Infiltration
Pancreas 2019 03;48(3):367-373
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30768574
OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a peritumoral proliferation of fibroblasts and extracellular matrix production known as desmoplasia. We aimed to study desmoplasia in PDAC lymph node (LN) metastases. METHODS: We evaluated LNs from 66 patients with PDAC and LN metastases. We used immunohistochemistry and real-time polymerase chain reaction to phenotype the desmoplastic response. RESULTS: Desmoplasia was identified in 57% of patients with LN metastases (Des+). Cancer-associated fibroblasts (CAFs) in Des+ expressed α-smooth muscle actin and collagen 11A1. The latter expression was present only in CAFs but not in LN stroma or in LN metastases without desmoplasia (Des-). Desmoplasia was associated with upregulation of transforming growth factor β messenger RNA. Whereas numbers of CD8+ in tumor vicinity were not different between Des+ and Des- patients (78 [standard deviation {SD}, 57] vs 92 [SD, 52], P = 0.48, respectively), the numbers of GATA-3+ cells, a marker of T-helper 2 immune response was significantly increased (3.7 [SD, 6.3] for Des+ vs 1.3 [SD, 2.7] for Des-, P < 0.05). CONCLUSIONS: Lymph node desmoplasia is associated with CAF pattern activation and Th2 infiltration. Therapeutic modulation of desmoplasia may be relevant in the metastatic phase and influence antitumor immune response.
29860986
- Immunotherapy and Prevention of Pancreatic Cancer
Trends in cancer 2018 06;4(6):418-428
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29860986
Pancreatic cancer is the third-leading cause of cancer mortality in the USA, recently surpassing breast cancer. A key component of pancreatic cancer’s lethality is its acquired immune privilege, which is driven by an immunosuppressive microenvironment, poor T cell infiltration, and a low mutational burden. Although immunotherapies such as checkpoint blockade or engineered T cells have yet to demonstrate efficacy, a growing body of evidence suggests that orthogonal combinations of these and other strategies could unlock immunotherapy in pancreatic cancer. In this Review article, we discuss promising immunotherapies currently under investigation in pancreatic cancer and provide a roadmap for the development of prevention vaccines for this and other cancers.
30243879
- Tumor-stromal cross-talk modulating the therapeutic response in pancreatic cancer
Hepatobiliary & pancreatic diseases international : HBPD INT 2018 Oct;17(5):461-472
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30243879
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant solid tumor with a dismal prognosis. The stroma component makes up to 90% of the tumor mass and is thought to be one of the main reasons for the tumor’s high chemoresistance. Cancer associated fibroblasts (CAFs) have previously been identified to be the key stromal players. This is the first time we provide detailed in vitro experiments investigating tumor-stromal interactions when exposed to three well-known chemotherapeutic agents. METHODS: Monocultures, indirect and direct co-cultures of two PDAC cell lines (AsPC and Panc-1) and six primary patients derived CAFs were treated with gemcitabine, nab-paclitaxel and the γ-secretase-inhibitor (GSI) DAPT. The cell viability of each component was measured with XTT. Finally, IL-6 concentrations of the supernatants were analyzed. RESULTS: On the contrary to PDAC cell lines, CAF monocultures hardly responded to any treatment which suggested that stroma (CAFs) itself is more resistant to standard chemo-treatments than the epithelial cancer cells. Moreover, only a weak chemotherapeutic response was observed in direct co-cultures of cancer cells with CAFs. A change in the morphology of direct co-cultures was accompanied with the chemoresistance. CAFs were observed to build cage-like structures around agglomerates of tumor cells. High levels of IL-6 were also associated with a reduced response to therapy. Indirect co-cultures make the tumor-stromal interaction more complex. CONCLUSIONS: CAFs are highly chemoresistant. Direct cell-cell contact and high levels of IL-6 correlate with a high chemoresistance.
30767148
- MiRNA-3653 Is a Potential Tissue Biomarker for Increased Metastatic Risk in Pancreatic Neuroendocrine Tumours
Endocrine pathology 2019 Jun;30(2):128-133
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30767148
Pancreatic neuroendocrine tumours (PNETs) are relatively uncommon, accounting for 1-2% of all pancreatic neoplasms. Tumour grade (based on the Ki67 proliferative index and mitotic rate) is associated with metastatic risk across large cohorts; however, predicting the behaviour of individual tumours can be difficult. Therefore, any tool which could further stratify metastatic risk may be clinically beneficial. We sought to investigate microRNA (miRNA) expression as a marker of metastatic disease in PNETs. Tumours from 37 patients, comprising 23 with locoregional disease (L) and 14 with distant metastases (DM), underwent miRNA profiling. In total 506 miRNAs were differentially expressed between the L and DM groups, with four miRNAs (miR-3653 upregulated, and miR-4417, miR-574-3p and miR-664b-3p downregulated) showing statistical significance. A database search demonstrated that miRNA-3653 was associated with ATRX abnormalities. Mean survival between the two groups was correlated with mean expression of miRNA-3653; however, this did not reach statistical significance (p = 0.204). Although this is a small study, we conclude that miRNA-3653 upregulation may be associated with an increased risk of metastatic disease in PNETS, perhaps through interaction with ATRX and the alternate lengthening of telomeres pathway.
29483829
- MiR-21-mediated Metabolic Alteration of Cancer-associated Fibroblasts and Its Effect on Pancreatic Cancer Cell Behavior
International journal of biological sciences 2018 01;14(1):100-110
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29483829
In this study, we investigated whether the metabolic alteration of cancer-associated fibroblasts (CAFs) occurs via miR-21 remodeling and the effect of this alteration on pancreatic cancer cells. CAFs and normal fibroblasts (NFs) were isolated and cultured. Glucose consumption and lactic acid production were tested, and lactate dehydrogenase (LDHA), pyruvate kinase m2 (PKM2), and miR-21 expression were examined. The level of glycolysis in CAFs was determined after treatment with a miR-21 inhibitor. Primary miR-21-NC CAFs and miR-21-inhibitor CAFs were indirectly co-cultured with BxPc-3 in vitro, and the invasion capacity of these cells was determined. The aerobic oxidation index of cancer cells and the expression of succinodehydrogenase (SDH) and fumarate hydratase (FH) were assessed. Compared with NFs, CAFs showed enhanced glucose uptake capacity, lactic acid production, and elevated LDHA, PKM2, and miR-21 expression. After miR-21 inhibitor treatment, the extent of glycolysis in CAFs was reduced. After indirect co-culture with CAFs, oxidative phosphorylation and SDH, FH, and MCT expression increased in BxPc-3 cells. After co-culture with miR-21-inhibitor-CAFs, oxidative phosphorylation and invasion ability of the pancreatic cancer cells decreased. MiR-21 was involved in metabolic alteration of CAFs and affected the development of cancer cells. This metabolic alteration may be an important mechanism by which the microenvironment promotes tumor progression in a nonvascular manner.
- Reply to The relationship between obesity in adolescence and pancreatic cancer in adulthood
Cancer 2019 Jun;125(12):2132-2133
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30768785
- Direct Interactions With Cancer-Associated Fibroblasts Lead to Enhanced Pancreatic Cancer Stem Cell Function
Pancreas 2019 Mar;48(3):329-334
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30747824
OBJECTIVE: Cancer-associated fibroblasts (CAFs) play an important role in the progression of pancreatic ductal adenocarcinoma (PDAC) by promoting tumor cell migration and drug resistance. We determined the impact of CAFs on PDAC cancer stem cells (CSCs). METHODS: Fibroblast cell lines from patients’ tumors were cocultured with PDAC cells and examined for clonogenic growth and self-renewal using colony-forming assays and migration in vitro. Changes in the frequency of CSCs was determined by flow cytometry. The effect of integrin-focal adhesion kinase (FAK) signaling on CAF-mediated clonogenic growth was evaluated using short hairpin RNAs against β1 integrin and FAK as well as a small-molecule FAK inhibitor. RESULTS: Cancer-associated fibroblasts enhanced PDAC clonogenic growth, self-renewal, and migration that was associated with an increase in the frequency of CSCs. These fibroblast cells were activated by PDAC cells and increased collagen synthesis resulting in FAK activation in PDAC cells. Knockdown of β1-integrin and FAK or the inhibition of FAK kinase activity in PDAC cells abrogated the impact of CAFs on clonogenic growth. CONCLUSION: Therefore, CAFs enhance PDAC clonogenic growth, self-renewal, and the frequency of CSCs through type I collagen production that enhances integrin-FAK signaling in PDAC cells.
- Overexpression of BUB1B, CCNA2, CDC20, and CDK1 in tumor tissues predicts poor survival in pancreatic ductal adenocarcinoma
Bioscience reports 2019 02;39(2):
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30765611
Overexpressed genes in tumors usually contributed to aggressiveness in pancreatic ductal adenocarcinoma (PDAC). Using Gene Expression Omnibus (GEO) profiles including GSE46234, GSE71989, and GSE107610, we detected overexpressed genes in tumors with R program, which were enriched by Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene ontology (GO), and Reactome pathway databases. Then, we performed a survival analysis of enriched genes based on TCGA profile. Our results revealed that high BUB1B, CCNA2, CDC20, and CDK1 expression in tumors was significantly associated with worse overall survival (OS) (Log rank P=0.00338, P=0.0447, P=0.00965, and P=0.00479, respectively), which was validated using a Kaplan-Meier plotter with a median cutoff (Log rank P=0.028, P=0.0035, P=0.039, and P=0.0033, respectively). Moreover, overexpression of BUB1B, CCNA2, CDC20, and CDK1 in tumor tissues was significantly associated with disease-free survival (DFS) in PDAC patients (Log rank P=0.00565, P=0.0357, P=0.00104, and P=0.00121, respectively). BUB1B, CCNA2, CDC20, and CDK1 were significantly overexpressed in deceased PDAC patients (all P<0.01) and in patients with recurrence/disease progression (all P<0.05). In addition, PDAC patients with neoplasms of histologic grade G3-4 had significantly higher BUB1B, CCNA2 and CDC20 levels (all P<0.05). In conclusion, the up-regulation of BUB1B, CCNA2, CDC20, CDK1, and WEE1 in tumor tissues are associated with worse OS and DFS in PDAC and is correlated with advanced tumor stage and tumor development.
30807303
- Intracholecystic Papillary Neoplasms Are Distinct From Papillary Gallbladder Cancers: A Clinicopathologic and Exome-sequencing Study
The American journal of surgical pathology 2019 Jun;43(6):783-791
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30807303
Although intracholecystic papillary neoplasms (ICPNs) have been increasingly recognized, their features remain unclear because of the lack of standardized definition. This study aimed to elucidate clinicopathologic and genetic features of ICPNs using stringent diagnostic criteria. On the basis of the recently proposed criteria, gallbladder neoplasms showing delicate papillary growth were diagnosed as ICPNs, while polypoid papillary adenocarcinomas arranged in a complex architecture were categorized as papillary gallbladder cancers (GBCs). Clinicopathologic features were compared among ICPNs (n=7), papillary GBCs (n=24), and nonpapillary GBCs (n=44). Whole-exome and validation Sanger sequencing was also conducted. Gross mucin hypersecretion was detected in 3/7 ICPNs (43%), 1/24 papillary GBCs (4%), and 1/44 nonpapillary GBCs (2%) (P<0.001). All patients with ICPN lacked lymphovascular invasion and nodal metastasis, while these features were occasionally observed in patients with papillary or nonpapillary GBC (13% to 59%). ICPNs were less advanced than papillary and nonpapillary GBCs (P<0.001) with all cases of ICPNs being recurrence-free. Whole-exome and Sanger sequencing identified somatic mutations in STK11 (a causative gene of Peutz-Jegher syndrome; n=3), CTNNB1 (n=2), and APC (a gene of familial adenomatous polyposis; n=1) in ICPNs, while those alterations were exceptional in papillary and nonpapillary GBCs. ICPNs more commonly showed cytoplasmic and/or nuclear expressions of β-catenin than papillary and nonpapillary GBCs. In conclusion, the histology-based classification of gallbladder papillary neoplasms is useful for identifying ICPNs that share clinicopathologic features with the pancreatic counterpart. ICPNs meeting the criteria were genetically distinct from papillary and nonpapillary GBCs, with STK11, CTNNB1, and APC being identified as major driver genes for ICPNs.
30805811
- Cellular Senescence, Represented by Expression of Caveolin-1, in Cancer-Associated Fibroblasts Promotes Tumor Invasion in Pancreatic Cancer
Annals of surgical oncology 2019 May;26(5):1552-1559
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30805811
BACKGROUND: The role of senescence of cancer-associated fibroblasts (CAFs) in the development of cancer is controversial. In this study, we investigated whether cellular senescence of CAFs, represented by CAV1 expression, affects tumor progression in pancreatic cancers (PC). METHODS: Because CAV1 plays a major role in cellular senescence, we used CAV1 expression to monitor cellular senescence. A total of 157 consecutive patients with PC who underwent curative resection were enrolled in the study. Patients were divided into two groups according to CAV1 expression in CAFs by immunohistochemistry. We investigated the relationship between the CAV1 expression in CAFs and the patients’ clinicopathological characteristics, including survival. We also established ten CAFs cell lines using PC clinical samples and chose one of them to knock down CAV1 expression. Finally, we cultured a PC cell line (MIAPaCa-2) in CAF-conditioned medium (CM). RESULTS: Regarding patients’ clinicopathological characteristics, the serum levels of carbohydrate antigen 19-9 and the rate of advanced tumor stage (pT2, 3, and 4) were significantly higher in the high-CAV1 group. The high-CAV1 group had significantly worse outcomes in both overall and disease-free survival (p < 0.01). Additionally, in co-culture assays using CAFs-CM and MIAPaCa-2 cells, we found that knockdown of CAV1 in CAFs negatively affected the invasion of PC cells. CONCLUSIONS: In PC, CAV1 expression in CAFs is associated with patients’ poor prognosis and the downregulation of CAV1 in CAFs reduces the invasiveness of PC cells. Therefore, CAV1 of CAFs might be a new target for the treatment of PC.
30803874
- Management and surveillance of non-functional pancreatic neuroendocrine tumours: Retrospective review
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Mar;19(2):360-366
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30803874
BACKGROUND: /Objective. To determine the outcomes of a non-operative management approach for sporadic, small, non-functional pancreatic neuroendocrine tumours. METHODS: A retrospective chart review of patients with non-functional pancreatic neuroendocrine tumours initially managed non-operatively at a single institution was performed. Patients were identified through a search of radiologic reports, and individuals with ≥2 cross-sectional imaging studies performed >6 months apart from Jan. 1, 2000 to Dec. 31, 2013 were included. Data on tumour size, radiologic characteristics at diagnosis, interval radiologic growth, and surgical outcomes were recorded. RESULTS: Over the thirteen-year study period, 95 patients met inclusion criteria and were followed radiologically for a median of 36 months (18-69 months). Median initial tumour size on first imaging was 14.0 mm (IQR 10-19 mm). Median overall tumour growth rate was 0.03 mm/month (IQR: 0.00-0.14 mm/month). There was no significant relationship between initial tumour size and growth rate for tumours ≤ 2 cm or for lesions between 2 and 4 cm. Thirteen (14%) patients initially managed non-operatively underwent resection during the follow-up period. Reasons for surgery included interval tumour growth, patient anxiety or preference, or diagnostic uncertainty. Median time to surgery was 14 months (IQR 8-19 months). No patients progressed beyond resectability or developed metastatic disease during the observation period. CONCLUSION: For patients with sporadic, small, non-functional pancreatic neuroendocrine tumours, radiologic surveillance appears to be a safe initial approach to management.
- Silencing of MUC20 suppresses the malignant character of pancreatic ductal adenocarcinoma cells through inhibition of the HGF/MET pathway
Oncogene 2018 11;37(46):6041-6053
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29993037
Mucins are heavily glycosylated proteins that play critical roles in the pathogenesis of tumour malignancies. Pancreatic ductal adenocarcinoma (PDAC) is characterised by the aberrant expression of mucins. However, the role of mucin (MUC) 20 in PDAC remains unclear. PDAC is usually surrounded by a dense fibrotic stroma consisting of an extracellular matrix and pancreatic stellate cells (PSCs). The stroma creates a nutrient-deprived, hypoxic, and acidic microenvironment, and promotes the malignant behaviours of PDAC cells. In this study, immunohistochemical staining demonstrated that high MUC20 expression correlated with poor progression-free survival and high local recurrence rate of PDAC patients (n = 61). The expression of MUC20 was induced by serum deprivation, hypoxia, and acidic pH in PDAC cells. MUC20 knockdown with siRNA decreased cell viability, as well as migration and invasion induced by PSCs in HPAC and HPAF-II cells. In intraperitoneal, subcutaneous, and orthotopic injection models, MUC20 knockdown decreased tumour growth in immunodeficient mice. Phospho-RTK array and western blot analysis indicated that MUC20 knockdown decreased HGF-mediated phosphorylation of MET in PDAC cells. Moreover, HGF-induced malignant phenotypes could be suppressed by MUC20 knockdown. Co-immunoprecipitation revealed the physical association of MUC20 and MET. These findings suggest that MUC20 knockdown suppresses the malignant phenotypes of PDAC cells at least partially through the inhibition of the HGF/MET pathway and that MUC20 could act as a potential therapeutic target.
30814496
- MTA2-mediated inhibition of PTEN leads to pancreatic ductal adenocarcinoma carcinogenicity
Cell death & disease 2019 Feb;10(3):206
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30814496
Metastasis-associated protein 2 (MTA2) is a core subunit of the nucleosome remodeling and deacetylating (NuRD) complex and functions by mediating chromatin remodeling and gene silencing. However, its biological actions and clinical significance in pancreatic ductal adenocarcinoma (PDAC) remain elusive. The aim of this study was to explore the function and regulation mechanism of MTA2 in PDAC. As shown in GEO, ICGC, and TCGA databases, a higher expression of MTA2 was noticed in the PDAC tissues than in the normal pancreatic tissues. Moreover, a higher expression level of MTA2 was associated with a shorter overall survival time in these public PDAC databases. We further investigated the underlying mechanisms of these observations by using a chromatin immunoprecipitation (ChIP)-based deep sequencing, luciferase reporter, and quantitative ChIP assays. We identified the repressive binding of MTA2 to the promoter of phosphatase and tensin homolog (PTEN). We also found that Snail recruited MTA2 and HDAC1 to suppress PTEN expression. Ectopic expression and knockdown of MTA2 were performed to evaluate the effects of this gene on PDAC cell proliferation, migration, and invasion. Using CCK-8, colony formation and transwell assays, and a xenograft tumor model, we revealed that MTA2 promoted PDAC cell proliferation, migration, and invasion in vitro and PDAC tumor growth in vivo by downregulation of PTEN. In benzyl isothiocyanate (BITC)-treated MIA Paca-2 cells and PANC-1 cells, MTA2 level decreased in a dose- and time-dependent manner with concomitant upregulation of PTEN level and downregulation of phosphorylated PI3K and AKT levels, providing evidence of the involvement of MTA2 and PTEN in the regulation of the PI3K/AKT pathway in BITC-mediated PDAC suppression. Collectively, these findings uncover a novel role for MTA2 in the regulation of PDAC progression and help to elucidate the mechanisms involved in this process.
- Is it time to standardize fine needle aspiration of gall bladder lesions and what city name it will be stamped with?
CytoJournal 2019 01;16():2
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30820232
- Intrahepatic Cholangiocarcinoma: Rising Burden and Glaring Disparities
Annals of surgical oncology 2019 Jul;26(7):1979-1980
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30820787
- Pancreatic Juice Exosomal MicroRNAs as Biomarkers for Detection of Pancreatic Ductal Adenocarcinoma
Annals of surgical oncology 2019 Jul;26(7):2104-2111
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30820789
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal neoplasm because of difficulties in early detection. Several studies have recently suggested that exosomes may have potential as novel biomarkers. This study aimed to isolate exosomes from pancreatic juice and to investigate whether exosomal microRNAs (ex-miRs) could be used as biomarkers for PDAC. METHODS: Pancreatic juice was collected from patients with PDAC and chronic pancreatitis (CP) by endoscopic retrograde pancreatography. Exosomes were extracted by ultracentrifugation. The presence of exosomes was confirmed by electron microscopy and Western blotting using anti-CD63, -CD81, and -TSG101 antibodies. Relative levels of ex-miR-21 and ex-miR-155 were quantified and compared between PDAC and CP patients. RESULTS: A total of 35 pancreatic juice samples (27 PDAC and 8 CP) were collected. Relative levels of both ex-miR-21 and ex-miR-155 were significantly higher in PDAC patients compared with CP patients (p < 0.001 and p = 0.008, respectively). By contrast, no significant difference was apparent in relative levels of miR-21 and miR-155 in whole pancreatic juice from PDAC patients compared with CP patients (p = 0.08 and p = 0.61, respectively). Ex-miR-21 and ex-miR-155 levels discriminated PDAC patients from CP patients with area under the curve values of 0.90 and 0.89, respectively. The accuracies of ex-miR-21 levels, ex-miR-155 levels, and pancreatic juice cytology were 83%, 89%, and 74%, respectively. When combining the results of ex-miR profiling with pancreatic juice cytology, the accuracy was improved to 91%. CONCLUSIONS: We successfully extracted exosomes from pancreatic juice. Ex-miRs, including ex-miR-21 and ex-miR-155, in pancreatic juice may be developed as biomarkers for PDAC.
- Is early-stage pancreatic adenocarcinoma truly early: stage migration on final pathology with surgery-first versus neoadjuvant therapy sequencing
HPB : the official journal of the International Hepato Pancreato Biliary Association 2019 Feb;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30799277
BACKGROUND: Neoadjuvant therapy (NT) remains controversial in early-stage pancreatic ductal adenocarcinoma (PDAC), defined as clinical (c)Stage I-II. Our aim was to analyze rates of pathologic upstaging/downstaging for resectable PDAC treated with surgery-first (SF) vs. NT. METHODS: Utilizing the National Cancer Data Base (NCDB), patients with cStage I-II PDAC who underwent pancreatoduodenectomy in 2006-2013 were pathologically staged using the AJCC 8th edition and compared by treatment sequencing. RESULTS: Among 13,871 patients, 15.3% received NT. Despite higher pre-treatment T-stage (cT2: 71.9% vs. 56.3%, p < 0.001), NT patients had lower rates of pathologic nodal metastases (46.2% vs. 69.2% in SF, p < 0.001), suggesting higher rates of pathologic downstaging. In cStage II, 33.0% were upstaged to stage III after SF, vs. only 14.0% after NT. In cStage I, 65.5% were upstaged following SF, vs. 46.7% after NT (all p < 0.001). Patients with NT (HR-0.77, p < 0.001) or downstaging (HR-0.80, p < 0.001) had improved overall survival (OS). CONCLUSION: NT is associated with reduction in unexpected upstaging, reduction in nodal positivity, and improved OS, compared to SF approach in putatively early-stage PDAC. Because clinical staging underestimates the underlying disease burden in resectable PDAC, patients with cStage I-II should be considered for NT.
- A tangled tale of molecular subtypes in pancreatic cancer
Gut 2019 06;68(6):953-954
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30814120
- BioMethyl: An R package for Biological Interpretation of DNA Methylation Data
Bioinformatics (Oxford, England) 2019 Feb;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30799505
MOTIVATION: The accumulation of publicly available DNA methylation data sets has resulted in the need for tools to interpret the specific cellular phenotypes in bulk tissue data. Current approaches use either single differentially methylated CpG sites or differentially methylated regions that map to genes. However, these approaches may introduce biases in downstream analyses of biological interpretation, because of the variability in gene length. There is a lack of approaches to interpret DNA methylation effectively. Therefore, we have developed computational models to provide biological interpretation of relevant gene sets using DNA methylation data in the context of The Cancer Genome Atlas (TCGA). RESULTS: We illustrate that biological interpretation of DNA methylation (BioMethyl) utilizes the complete DNA methylation data for a given cancer type to reflect corresponding gene expression profiles and performs pathway enrichment analyses, providing unique biological insight. Using breast cancer as an example, BioMethyl shows high consistency in the identification of enriched biological pathways from DNA methylation data compared to the results calculated from RNA sequencing data. We find that 12 out of 14 pathways identified by BioMethyl are shared with those by using RNA-seq data, with a Jaccard score 0.8 for estrogen receptor (ER) positive samples. For ER negative samples, three pathways are shared in the two enrichments with a slight lower similarity (Jaccard score=0.6). Using BioMethyl, we can successfully identify those hidden biological pathways in DNA methylation data when gene expression profile is lacking. AVAILABILITY: BioMethyl R package is freely available in the GitHub repository (https://github.com/yuewangpanda/BioMethyl). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
- Statistical Guidance for Reviewers of Toxicologic Pathology
Toxicologic pathology 2018 08;46(6):647-652
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29966505
Study design, statistical analysis, interpretation of results, and conclusions should be a part of all research papers. Statistics are integral to each of these components and are therefore necessary to evaluate during manuscript peer review. Research published in Toxicological Pathology is often focused on animal studies that may seek to compare defined treatment groups in randomized controlled experiments or focus on the reliability of measurements and diagnostic accuracy of observed lesions from preexisting studies. Reviewers should distinguish scientific research goals that aim to test sufficient effect size differences (i.e., minimizing false positive rates) from common toxicologic goals of detecting a harmful effect (i.e., minimizing false negative rates). This journal comprises a wide range of study designs that require different kinds of statistical assessments. Therefore, statistical methods should be described in enough detail so that the experiment can be repeated by other research groups. The misuse of statistics will impede reproducibility.
https://www.sciencedirect.com/science/article/abs/pii/S1365182X19300024
http://cancerres.aacrjournals.org/content/early/2019/02/14/0008-5472.CAN-18-2553.short
https://www.sciencedirect.com/science/article/pii/S1424390319300316
https://www.nature.com/articles/s41598-019-38603-w
https://jitc.biomedcentral.com/articles/10.1186/s40425-019-0521-4
https://europepmc.org/abstract/ppr/ppr70162
https://www.nature.com/articles/s41575-019-0109-y
https://onlinelibrary.wiley.com/doi/abs/10.1111/pin.12768
https://www.sciencedirect.com/science/article/pii/S221112471930066X
https://www.sciencedirect.com/science/article/pii/S2210261219300495
https://www.sciencedirect.com/science/article/pii/S0016508519303592
https://link.springer.com/article/10.1007/s11605-019-04113-3
https://www.gastrojournal.org/article/S0016-5085(19)30353-1/fulltext
https://www.nature.com/articles/s41388-019-0725-6
https://www.gastrojournal.org/article/S0016-5085(19)30351-8/fulltext
https://www.nature.com/articles/s41388-019-0718-5
https://www.karger.com/Article/Abstract/496507
https://www.sciencedirect.com/science/article/pii/S1072751519301498
- Wnt/β-catenin signalling plays diverse functions during the process of fibrotic remodelling in the exocrine pancreas
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Mar;19(2):252-257
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30792046
BACKGROUND/OBJECTIVES: Wnt/β-catenin signalling plays vital roles in tissue homeostasis. Dysregulation of the pathway has been implicated in the pathogenesis of cancer and fibroses in numerous tissues, including the pancreas. We studied the effect of microenvironmental changes pertaining to fibrotic tissue remodelling on the expression of selected Wnt/β-catenin pathway proteins in the human exocrine pancreas. The role of acinar/stellate cross-talk on the expression of the proteins was elucidated in a long-term mouse co-culture system. METHODS: Expression of β-catenin, Wnt2, Wnt5a and SFRP4 was analysed immunohistochemically in normal and moderately or highly fibrotic human pancreata (n = 8). The effect of humoral interactions on the expression of the proteins was studied by immunocytochemical means in parallel mono- and co-cultures of mouse acinar and stellate cells (PSCs). RESULTS: In human pancreatic tissue, fibrotic microenvironment was associated with redistribution of the proteins in and between epithelial and stromal compartments, compared to acinar-rich tissue. In non-fibrotic and moderately fibrotic tissue the proteins appeared only in acinar cells whereas in highly fibrotic tissue stromal fibroblastoid/stellate cells and macrophages were their predominant locations. Subcellular changes in the expression of β-catenin and Wnt5a were detected. Our in vitro data suggest potential involvement of acinar cell/PSC cross-talk in mediating the changes observed in tissue specimens. CONCLUSIONS: Wnt/β-catenin pathway-associated proteins are abundantly expressed in the exocrine pancreas with prominent changes in their cellular and subcellular expression patterns along with increasing levels of fibrosis. Diverse functions for Wnt/β-catenin signalling during the course of fibrotic remodelling in the exocrine pancreas are suggested.
- The value of cytology in the management of patients with pancreatic cysts
Cancer cytopathology 2019 Mar;127(3):141-142
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30668886
- Integration of Genomic and Transcriptional Features in Pancreatic Cancer Reveals Increased Cell Cycle Progression in Metastases
Cancer cell 2019 Feb;35(2):267-282.e7
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30686769
We integrated clinical, genomic, and transcriptomic data from 224 primaries and 95 metastases from 289 patients to characterize progression of pancreatic ductal adenocarcinoma (PDAC). Driver gene alterations and mutational and expression-based signatures were preserved, with truncations, inversions, and translocations most conserved. Cell cycle progression (CCP) increased with sequential inactivation of tumor suppressors, yet remained higher in metastases, perhaps driven by cell cycle regulatory gene variants. Half of the cases were hypoxic by expression markers, overlapping with molecular subtypes. Paired tumor heterogeneity showed cancer cell migration by Halstedian progression. Multiple PDACs arising synchronously and metachronously in the same pancreas were actually intra-parenchymal metastases, not independent primary tumors. Established clinical co-variates dominated survival analyses, although CCP and hypoxia may inform clinical practice.
- Pancreatic cancer stem cells: A state or an entity?
Seminars in cancer biology 2018 12;53():223-231
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30130664
Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, has a median overall survival of 6-12 months and a 5-year survival of less than 7%. While PDAC currently represents the 4th most frequent cause of death due to cancer worldwide, it is expected to become the second leading cause of cancer-related death by 2030. These alarming statistics are primarily due to both the inherent chemoresistant and metastatic nature of this tumor, and the existence of a subpopulation of highly plastic “stem”-like cells within the tumor, known as cancer stem cells (CSCs). Since their discovery in PDAC in 2007, we have come to realize that pancreatic CSCs have unique metabolic, autophagic, invasive, and chemoresistance properties that allow them to continuously self-renew and escape chemo-therapeutic elimination. More importantly, the concept of the CSC as a fixed entity within the tumor has also evolved, and current data suggest that CSCs are states rather than defined entities. Consequently, current treatments for the majority of PDAC patients are not effective, and do not significantly impact overall patient survival, as they do not adequately target the plastic CSC sub-population nor the transient/hybrid cells that can replenish the CSC pool. Thus, it is necessary that we improve our understanding of the characteristics and signals that maintain and drive the pancreatic CSC population in order to develop new therapies to target these cells. Herein, we will provide the latest updates and knowledge on the inherent characteristics of pancreatic CSCs and the CSC niche, specifically the cross-talk that exists between CSCs and niche resident cells. Lastly, we will address the question of whether a CSC is a state or an entity and discuss how the answer to this question can impact treatment approaches.
https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.32127
https://europepmc.org/abstract/med/30672796
https://onlinelibrary.wiley.com/doi/abs/10.1002/dc.24145
https://www.nature.com/articles/s41388-019-0701-1
http://ascopubs.org/doi/abs/10.1200/PO.18.00240
https://www.nature.com/articles/s41379-018-0196-2
https://link.springer.com/article/10.1007/s12328-019-00936-4
https://res.mdpi.com/cancers/cancers-11-00113/article_deploy/cancers-11-00113.pdf
https://www.nature.com/articles/s41389-018-0117-8
https://www.sciencedirect.com/science/article/pii/S0016508518351606
https://www.mdpi.com/2072-6694/11/1/113
http://mcr.aacrjournals.org/content/early/2019/01/17/1541-7786.MCR-18-0367.abstract
https://www.nature.com/articles/s41467-018-08109-6
https://www.sciencedirect.com/science/article/pii/S0304383519300138
https://jeccr.biomedcentral.com/articles/10.1186/s13046-018-0986-x
https://www.sciencedirect.com/science/article/pii/S0748798319300101
https://www.ncbi.nlm.nih.gov/pubmed/30640232
https://www.ncbi.nlm.nih.gov/pubmed/30640227
https://www.sciencedirect.com/science/article/pii/S1542356519300072
https://www.sciencedirect.com/science/article/pii/S2214330018301597
https://link.springer.com/article/10.1186/s12885-018-5195-7
https://link.springer.com/article/10.1007/s00262-018-2290-1
https://www.cghjournal.org/article/S1542-3565(18)30498-1/fulltext
http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=26503
https://www.nature.com/articles/s41467-018-07472-8
https://onlinelibrary.wiley.com/doi/abs/10.1111/apm.12900
https://www.pnas.org/content/early/2018/12/11/1812915116.short
Oncogene volume 37, pages 6041–6053 (2018)
https://www.nature.com/articles/s41388-018-0403-0
https://gut.bmj.com/content/early/2018/11/05/gutjnl-2018-316822
https://www.nature.com/articles/s41388-018-0553-0
http://cancerres.aacrjournals.org/content/canres/early/2018/10/24/0008-5472.CAN-18-1968.full.pdf
https://gut.bmj.com/content/early/2018/10/20/gutjnl-2018-316128
https://www.nature.com/articles/s41389-018-0096-9
https://www.nature.com/articles/s41416-018-0262-z
https://www.sciencedirect.com/science/article/pii/S0960740418301245
https://onlinelibrary.wiley.com/doi/abs/10.1002/jso.25312
https://www.sciencedirect.com/science/article/pii/S0002944018301512
https://journals.lww.com/eurojgh/Abstract/2019/01000/The_efficacy_and_safety_of_endoscopic.1.aspx
https://www.sciencedirect.com/science/article/pii/S193004331830373X
https://www.sciencedirect.com/science/article/pii/S1590865818312672
https://www.sciencedirect.com/science/article/pii/S0002944018301561
https://gut.bmj.com/content/early/2018/12/07/gutjnl-2018-317735
https://www.sciencedirect.com/science/article/pii/S0021997518302020
https://www.sciencedirect.com/science/article/pii/S0002944018302025
https://www.hindawi.com/journals/grp/2018/7530619/
https://www.hindawi.com/journals/amed/2018/7539694/
https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.32072
https://www.sciencedirect.com/science/article/pii/S1877782118305101
https://onlinelibrary.wiley.com/doi/10.1111/cyt.12675
https://cancerci.biomedcentral.com/articles/10.1186/s12935-018-0718-5
http://www.impactjournals.com/Genes&Cancer/files/papers/1/184/184.pdf
https://www.sciencedirect.com/science/article/pii/S0304383518307201
December 2018Oncotarget 9(102) DOI: 10.18632/oncotarget.26503
https://casereports.bmj.com/content/11/1/e226369
https://www.biorxiv.org/content/biorxiv/early/2019/01/15/521831.full.pdf
https://journals.sagepub.com/doi/pdf/10.1177/2050640618824910
https://link.springer.com/article/10.1186/s40169-019-0221-1
https://onlinelibrary.wiley.com/doi/10.1002/jso.25376
https://www.sciencedirect.com/science/article/pii/S0304383519300254
https://www.sciencedirect.com/science/article/pii/S0748798319300411
https://www.sciencedirect.com/science/article/pii/S0016508519300563
https://www.sciencedirect.com/science/article/pii/S2210261219300331
- Pathomorphological features of metastatic lymph nodes as predictors of postoperative prognosis in pancreatic cancer
Medicine 2019 Feb;98(5):e14369
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30702628
To investigate the pathological features of metastatic lymph nodes (LN) in pancreatic ductal adenocarcinoma (PDAC) and to determine factors with prognostic implications.Metastatic LN status is a proven significant factor for predicting postoperative prognosis in pancreatic cancer patients. However, the effective prognostic criteria regarding metastatic LNs for such disease remain unknown.We retrospectively reviewed 98 patients with R0/1 resection for PDAC. All metastatic LNs were evaluated for the pathomorphological features of metastasis and analyzed in terms of postoperative outcomes. Various morphological patterns of metastasis were assessed in 440 positive LNs and then classified into 4 groups: common type, direct type (continuously invaded by the main tumor), scatter type (multiple tumor clusters among the normal LN tissues), and isolated tumor cell (ITC).The pathological stage was defined as stage IIA in 10% and IIB in 90% patients. Common-type metastasis was noted in 55% positive LNs of 75% node-positive patients; direct type in 36% LNs of 69% patients; scatter type in 5% LNs of 14% patients; and ITCs in 5% LNs of 18% patients. Significant difference was noted only in recurrence-free survival (RFS) but not in overall survival (OS) in the common-type; only in OS but not in RFS for the scatter type; and neither in RFS nor OS for both direct type and ITC. Multivariate analysis revealed that only LN ratio and curability were independent predictive factors of poor.The tumor distribution patterns in metastatic LNs are the postoperative prognostic factors in pancreatic cancer.
https://onlinelibrary.wiley.com/doi/abs/10.1002/prca.201800046
https://onlinelibrary.wiley.com/doi/abs/10.1002/prca.201970013
- Pancreatitis in Children
Gastroenterology 2019 05;156(7):1969-1978
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30716320
Acute, acute recurrent, and chronic forms of pancreatitis have been increasingly diagnosed in children in the past 2 decades. Risk factors in the pediatric group are broad and appear to be strikingly different compared with the adult cohort. However, the disease burden and impact on quality of life are surprisingly similar in children and adults. This review summarizes the definitions, epidemiology, risk factors, diagnosis, and management of pediatric pancreatitis, identifies features that are unique to the childhood-onset disease, identifies gaps, and proposes recommendations for future opportunities.
https://www.sciencedirect.com/science/article/pii/S0305737219300519
https://bmccancer.biomedcentral.com/articles/10.1186/s12885-019-5455-1
https://www.sciencedirect.com/science/article/abs/pii/S0046817719300875
https://link.springer.com/article/10.1007/s11605-019-04235-8
https://academic.oup.com/ajcp/advance-article-abstract/doi/10.1093/ajcp/aqz032/5492096
https://www.ingentaconnect.com/contentone/sesc/tas/2019/00000085/00000005/art00029
https://www.ncbi.nlm.nih.gov/pubmed/30889123
https://onlinelibrary.wiley.com/doi/abs/10.1111/liv.14085
https://www.ncbi.nlm.nih.gov/pubmed/30884200
https://www.ncbi.nlm.nih.gov/pubmed/30881041
https://link.springer.com/article/10.1007/s00268-019-04966-4
https://www.surgical.theclinics.com/article/S0039-6109(18)30170-1/abstract
- Intrahepatic Cholangiocarcinoma: Socioeconomic Discrepancies, Contemporary Treatment Approaches and Survival Trends from the National Cancer Database
Annals of surgical oncology 2019 Jul;26(7):1993-2000
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30693451
OBJECTIVE: The aim of this study was to evaluate socioeconomic discrepancies in current treatment approaches and survival trends among patients with intrahepatic cholangiocarcinoma (ICC). METHODS: The 2004-2015 National Cancer Database was retrospectively analyzed for histopathologically proven ICC. Treatment predictors were evaluated using multinomial logistic regression and overall survival via multivariable Cox models. RESULTS: Overall, 12,837 ICC patients were included. Multiple factors influenced treatment allocation, including age, education, comorbidities, cancer stage, grade, treatment center, and US state region (multivariable p < 0.05). The highest surgery rates were observed in the Middle Atlantic (28.7%) and lowest rates were observed in the Mountain States (18.4%). Decreased ICC treatment likelihood was observed for male African Americans with Medicaid insurance and those with low income (multivariable p < 0.05). Socioeconomic treatment discrepancies translated into decreased overall survival for patients of male sex (vs. female; hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.16-1.26, p < 0.001), with low income (< $37,999 vs. ≥ $63,000 annually; HR 1.07, 95% CI 1.01-1.14, p = 0.032), and with Medicaid insurance (vs. private insurance; HR 1.13, 95% CI 1.04-1.23, p = 0.006). Both surgical and non-surgical ICC management showed increased survival compared with no treatment, with the longest survival for surgery (5-year overall survival for surgery, 33.5%; interventional oncology, 11.8%; radiation oncology/chemotherapy, 4.4%; no treatment, 3.3%). Among non-surgically treated patients, interventional oncology yielded the longest survival versus radiation oncology/chemotherapy (HR 0.73, 95% CI 0.65-0.82, p < 0.001). CONCLUSIONS: ICC treatment allocation and outcome demonstrated a marked variation depending on socioeconomic status, demography, cancer factors, and US geography. Healthcare providers should address these discrepancies by providing surgery and interventional oncology as first-line treatment to all eligible patients, with special attention to the vulnerable populations identified in this study.
https://onlinelibrary.wiley.com/doi/abs/10.1002/bjs.11063
https://onlinelibrary.wiley.com/doi/abs/10.1111/his.13827?af=R
https://onlinelibrary.wiley.com/doi/abs/10.1111/his.13827?af=R
https://link.springer.com/article/10.1007/s00268-019-04913-3
https://casereports.bmj.com/content/12/1/bcr-2018-227063.abstract
https://link.springer.com/article/10.1007/s12029-018-00199-1
https://link.springer.com/article/10.1007/s12328-018-00928-w
https://www.sciencedirect.com/science/article/pii/S0022480418307753
http://ascopubs.org/doi/abs/10.1200/JCO.2019.37.4_suppl.281
- Intrahepatic cholangiocarcinoma: the AJCC/UICC 8th edition updates
Chinese clinical oncology 2018 Oct;7(5):52
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30180751
Intrahepatic cholangiocarcinoma accounts for 5% to 30% of all primary liver cancers, and its incidence has increased in the last 3 decades. Surgical resection remains the only potentially curative treatment but is associated with high tumor recurrence rates. The 7th edition of the American Joint Committee on Cancer (AJCC) Staging Manual introduced a new staging system for intrahepatic cholangiocarcinoma, which was previously staged the same as hepatocellular carcinoma. The recently published 8th edition has subdivided the T1 category to T1a and T1b based on a size cutoff of 5 cm, removed periductal invasion from the T4 category, and downstaged T4 tumors and regional lymph node metastasis from stage IV to IIIB. Continued international efforts to accurately stratify prognosis are important to counsel patients and guide treatment decisions.
https://diagnosticpathology.biomedcentral.com/articles/10.1186/s13000-019-0813-5
- Importance of routine histopathological examination of a gallbladder surgical specimen: Unexpected gallbladder cancer
Journal of cancer research and therapeutics 2018 11;14(6):1325-1329
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30488851
Introduction: Cholecystectomy performed for benign diseases of the gallbladder is important for the diagnosis of gallbladder cancer. This is done by pathological examination of the removed specimens for patients with no detected or suspected complications before surgery. Although some centers undertake selective approaches for histopathological examination of gallbladder specimens, many centers perform this examination routinely. In our study, we investigated results of pathological examinations carried out on cholecystectomy specimens, in respect to unexpected cases of gallbladder cancer. Methods: We reviewed cholecystectomy cases performed for benign diseases of gallbladder from January 2012 to February 2016 by investigating pathological specimens from the gallbladder. We evaluated demographical properties and their association with the pathological diagnosis and frequency of unexpected gallbladder cancer cases. We reported additional treatment and survival information of the malignancy cases after surgery. Results: We reviewed 1294 cases of cholecystectomy, and the mean patient age was 47.5 ± 14.3 years. The most frequent diagnosis was chronic cholecystitis (92.3%), and it was more prevalent among younger patients and female sex (P < 0.0001). Five patients (0.4%) were determined to have gallbladder cancer, and the mean age of these cases was 65.6 ± 18.2 years. Two cases were Stage 2, two cases were Stage 3B, and one case was Stage 3A. There was no T1 or Tis tumor. Conclusion: Routine histopathological examination of gallbladder is significant with respect to the determination of additional interventions at the postoperative period required for cancer cases coincidentally diagnosed.
https://wjso.biomedcentral.com/articles/10.1186/s12957-019-1598-4
IL-33 overexpression in gallbladder cancers associated with pancreatobiliary maljunction.
https://www.ncbi.nlm.nih.gov/pubmed/30882917
https://www.ncbi.nlm.nih.gov/pubmed/30887297
https://link.springer.com/chapter/10.1007/978-981-13-5877-7_2
https://onlinelibrary.wiley.com/doi/abs/10.1002/jso.25450
https://www.ncbi.nlm.nih.gov/pubmed/30820233
https://www.surgical.theclinics.com/article/S0039-6109(18)30178-6/fulltext
https://pubs.rsna.org/doi/abs/10.1148/rg.2019180164
https://www.karger.com/Article/FullText/495523
https://www.sciencedirect.com/science/article/pii/S0748798319300368
https://link.springer.com/article/10.1007/s12079-018-00503-5
https://onlinelibrary.wiley.com/doi/10.1111/his.13797
https://onlinelibrary.wiley.com/doi/abs/10.1002/jhbp.593
https://www.tandfonline.com/doi/abs/10.1080/15513815.2019.1588442?journalCode=ipdp20
https://www.ncbi.nlm.nih.gov/pubmed/30918431
https://journals.lww.com/ajsp/Abstract/2019/06000/Neuroendocrine_Tumors__NETs__of_the_Minor.1.aspx
https://ascopubs.org/doi/pdfdirect/10.1200/PO.18.00323
- [Combined application of immunohistochemical markers to identify pathologic subtypes of ampullary carcinoma and its clinical significance]
Zhonghua bing li xue za zhi = Chinese journal of pathology 2019 Feb;48(2):92-97
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30695858
Objective: To investigate the expression of immunomarkers CK7, CK20, CK17, CDX2, MUC1 and MUC2 in primary adenocarcinoma of the ampulla of Vater, to explore the role of these markers in the histopathologic subclassification of ampullary carcinoma; and to provide biologic basis for precision treatment of patients with different types of ampullary carcinoma. Methods: Forty-two cases of primary ampullary carcinoma were collected at Peking University People’s Hospital, from 2012 to 2018 year. There were 22 males and 20 females. Aged range 42 to 88 years old, with mean aged (62±11) years. Among the patients, 6 was high differentiation, 19 median differentiation, and 17 low differentiation. Immunohistochemical studies on the expression of CK7, CK20, CK17, CDX2, MUC1 and MUC2 were performed in 42 cases of primary ampullary carcinoma. The relationship between different ampullary carcinoma subtypes and clinicopathologic survival data was analyzed using SPSS 16.0 statistical software. Results: Three histopathologic subtypes were observed. Among 42 cases, 8(19.0%)were classified as intestinal subtype, which showed a positive expression rate of 8/8 for both CK20 and CDX2, and 5/8 for MUC2. Both CK7 and CK17 were weakly expressed in one case (1/8). No expression was observed for MUC1 in this subtype. Twenty-two (52.4%,22/42) cases were classified as pancreaticobiliary subtype, which showed a positive expression rate of 100.0%(22/22) for both CK7 and MUC1, and 90.9% (20/22) for CK17. No expression was observed for CK20, CDX2 and MUC2.The remaining 12 (28.6%) cases were classified as mixed subtype, which showed variable expression patterns. The expression frequencies of these 6 immunomarkers in different subtypes of ampullary carcinoma did not correlate with various clinicopathologic factors such as patient gender and age, tumor size, histologic differentiation, pancreatic and bile duct invasion, or the depth of duodenal invasion. However, stage Ⅲ+Ⅳ diseases were more commonly seen in pancreaticobiliary type (63.6%,14/22) than intestinal type (2/8) and mixed type (3/9; χ(2)=6.508, P=0.039). Follow-up data showed a trend of better survival rate for patients with intestinal subtype than those with mixed and pancreaticobiliary subtypes. Conclusions: Ampullary carcinoma can be subclassified into three different subtypes using a panel of six immunomarkers, especially for the identification of subtypes of poorly differentiated carcinoma. CK7, CK17 and MUC1 are major markers of pancreaticobiliary subtype, whereas CK20, CDX2 and MUC2 are useful markers for intestinal subtype. The mixed subtype variably expresses these markers. The prognosis of patients with intestinal subtype appears better than that of pancreaticobiliary and mixed subtypes. Accurate subtyping of ampullary carcinoma is clinically important to patient management and prognosis assessment.
Adenosquamous carcinoma of the papilla of Vater: A phenotypic heterogeneity characterized by a common molecular landscape.
https://www.ncbi.nlm.nih.gov/pubmed/30417956
https://www.nature.com/articles/s41416-019-0415-8
https://www.gastrores.org/index.php/Gastrores/article/view/1129/1159
https://link.springer.com/article/10.1245/s10434-019-07238-6
https://link.springer.com/article/10.1245/s10434-019-07241-x
- Gastric-type adenocarcinoma of the duodenum arising from Brunner glands
Pathology international 2019 03;69(3):177-179
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30694586
- The Role of Log Odds of Positive Lymph Nodes in Predicting the Survival after Resection for Ampullary Adenocarcinoma
Pathology oncology research : POR 2019 Jan;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30693420
Lymph node metastasis is a important factor on survival in ampullary adenocarcinoma. Log odds of positive lymph nodes (LODDS) is a novel prognostic indicator on lymph node status. We aimed to evaluate the prognostic impact of LODDS for the patients with ampullary adenocarcinoma who underwent R0 pancreaticoduodenectomy. The study includes 42 patients.. LODDS was calculated as “log (number of metastatic lymph nodes+0.5)/(number of total harvested nodes - metastatic lymph nodes+0.5)”. LODDS subgroups were created based on their LODDS value: LODDS1(LODDS≤ - 1.5), LODDS2(-1.5 < LODDS≤ - 1.0), LODDS3(-1.0 < LODDS≤ - 0.5), LODDS4(LODDS> - 0.5). The mean survival time was 72.7 ± 7.82 months. Survival rates for 1, 3 and 5 years were 93%, 65% and 45%, respectively. The mean LODDS value was -1.0466 ± 0.51. LODDS subgroups show strong correlation with Overall Survival(OS). The mean survival were 114.8, 81.8, 56.6 and 25.6 months in LODDS subgroups 1, 2, 3 and 4, respectively (Log-rank; p = 0.002), in addition LOODS values shows correlation with perineural invasion and micro vascular invasion (p = 0.015 and p = 0.001 respectively). Findings in our patient group support the hypothesis that LODDS subgroups correlate with OS, and that value of LODDS has considerable role in prediction of OS as well.
https://www.sciencedirect.com/science/article/pii/S1424390319300201
https://link.springer.com/article/10.1007/s12253-019-00584-6
https://onlinelibrary.wiley.com/doi/abs/10.1002/cncr.31951
https://onlinelibrary.wiley.com/doi/10.1111/pin.12731
https://onlinelibrary.wiley.com/doi/abs/10.1002/jso.25311
https://onlinelibrary.wiley.com/doi/abs/10.1002/jso.25336
https://link.springer.com/article/10.1007/s00262-018-02293-6
- Predictors of long-term survival after pancreaticoduodenectomy for peri-ampullary adenocarcinoma: A retrospective study of 5-year survivors
Hepatobiliary & pancreatic diseases international : HBPD INT 2018 Oct;17(5):443-449
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30126828
BACKGROUND: Pancreaticoduodenectomy (PD) is the standard curative treatment for periampullary tumors. The aim of this study is to report the incidence and predictors of long-term survival (≥ 5 years) after PD. METHODS: This study included patients who underwent PD for pathologically proven periampullary adenocarcinomas. Patients were divided into 2 groups: group (I) patients who survived less than 5 years and group (II) patients who survived ≥ 5 years. RESULTS: There were 47 (20.6%) long-term survivors (≥ 5 years) among 228 patients underwent PD for periampullary adenocarcinoma. Patients with ampullary adenocarcinoma represented 31 (66.0%) of the long-term survivors. Primary analysis showed that favourable factors for long-term survival include age < 60 years old, serum CEA < 5 ng/mL, serum CA 19-9 < 37 U/mL, non-cirrhotic liver, tumor size < 2 cm, site of primary tumor, postoperative pancreatic fistula, R0 resection, postoperative chemotherapy, and no recurrence. Multivariate analysis demonstrated that CA 19-9 < 37 U/mL [OR (95% CI) = 1.712 (1.248-2.348), P = 0.001], smaller tumor size [OR (95% CI )= 1.335 (1.032-1.726), P = 0.028] and Ro resection [OR (95% CI) = 3.098 (2.095-4.582), P < 0.001] were independent factors for survival ≥ 5 years. The prognosis was best for ampullary adenocarcinoma, for which the median survival was 54 months and 5-year survival rate was 39.0%, and the poorest was pancreatic head adenocarcinoma, for which the median survival was 27 months and 5-year survival rate was 7%. CONCLUSIONS: The majority of long-term survivors after PD for periampullary adenocarcinoma are patients with ampullary tumor. CA 19-9 < 37 U/mL, smaller tumor size, and R0 resection were found to be independent factors for long-term survival ≥ 5 years.
- Ectopic papilla of Vater in duodenum bulb: A hospital-based study
Medicine 2019 Feb;98(8):e14642
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30813203
The major papilla of Vater can be ectopically present in the stomach, pyloric canal, duodenal bulb, and third or fourth portion of the duodenum. In this study, we determined the clinical significance of ectopic papilla of Vater by endoscopic retrograde cholangiopancreatogram (ERCP).A retrospective study was conducted by reviewing the medical records of 6133 patients receiving ERCP from 1988 to 2011. The diagnosis was confirmed if both the common bile duct (CBD) and the main pancreatic duct (PD) drained into the same opening, either by ERCP or magnetic resonance cholangiopancreatography.Eight patients with major papilla of Vater in the duodenal bulb were identified among 6133 patients receiving ERCP from 1988 to 2011, with an incidence rate of 0.13%. The mean age was 67 years and patients were predominantly male. Duodenal bulb deformity was noted in all patients and three of them had shallow gastric and/or duodenal ulcers. Hook-shaped CBD configuration was seen only in half of our cases. Three patients with CBD stones were treated successfully after endoscopic sphincterotomy or papillary balloon dilation.Ectopic orifice of papilla is a rare finding of ERCP. Opacification of both the CBD and main PD from the same opening is an essential criterion for diagnosing an ectopic papilla of Vater in the duodenal bulb.
- Ampullary Cancer
The Surgical clinics of North America 2019 Apr;99(2):357-367
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30846039
Compared with other periampullary tumors, cancers of the ampulla of Vater are rare. These tumors tend to present earlier than their pancreatic and distal bile duct brethren. In addition to the hypothesis that they are also less biologically aggressive, ampullary cancers tend to have better survival than other types of periampullary cancers. The mortality from this disease remains high, and much can still be learned about ampullary cancers.
- Recurrence patterns after pancreaticoduodenectomy for ampullary cancer
Journal of hepato-biliary-pancreatic sciences 2019 May;26(5):179-186
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30849209
BACKGROUND: Few studies of the oncological outcomes of ampullary cancer have addressed recurrence, and many treatment-related issues remain unresolved. This study evaluated optimal surgical treatment strategies based on recurrence patterns after pancreaticoduodenectomy (PD) for ampullary cancer. METHODS: Two hundred and fifty-nine patients who underwent PD with R0 resection for ampullary cancer from January 2000 to June 2012 were included. Generally, lymph node (LN) dissection extended to the right superior mesenteric artery (SMA). Recurrence was defined based on imaging studies. The first detected recurrence sites and patterns were analyzed. RESULTS: During a mean follow-up of 51.3 months, recurrence occurred in 89 (34.4%) cases, most commonly in the liver. Poor differentiation, advanced T stage, and LN metastasis were identified as risk factors for recurrence. Locoregional and systemic recurrences occurred alone or simultaneously in 20.2%, 73.0%, and 6.7% of patients, respectively. Locoregional and systemic recurrences tended to occur in early- and advanced-stage cases, respectively. A nodal-type recurrence around mesenteric vessels was the most common locoregional recurrence pattern, and 58.8% (10/17) were located left of the SMA. CONCLUSION: As nodal-type metastasis around the mesenteric vessels was the dominant recurrence pattern, careful LN dissection around the SMA should be considered for early and advanced ampullary cancers.
https://www.ncbi.nlm.nih.gov/pubmed/29459559
https://onlinelibrary.wiley.com/doi/abs/10.1111/his.13899
https://www.sciencedirect.com/science/article/pii/S0003426619300629
https://www.ncbi.nlm.nih.gov/pubmed/30894303
https://www.surgjournal.com/article/S0039-6060(18)30747-5/fulltext
https://www.ncbi.nlm.nih.gov/pubmed/30863939
https://www.nature.com/articles/s41571-019-0186-4
https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1034-4
https://dm5migu4zj3pb.cloudfront.net/manuscripts/123000/123049/JCI123049.v1.pdf
https://link.springer.com/article/10.1245%2Fs10434-018-6941-4
http://clincancerres.aacrjournals.org/content/early/2019/01/19/1078-0432.CCR-18-1401
https://academic.oup.com/edrv/advance-article-abstract/doi/10.1210/er.2018-00160/5289720
https://bmccancer.biomedcentral.com/articles/10.1186/s12885-018-5257-x
https://www.kjronline.org/DOIx.php?id=10.3348/kjr.2018.0040
https://www.sciencedirect.com/science/article/pii/S0039606018307475
https://www.spandidos-publications.com/10.3892/ol.2018.9795
https://www.sciencedirect.com/science/article/pii/S0039606018307475
https://link.springer.com/article/10.1007/s12328-018-0927-4
https://www.sciencedirect.com/science/article/pii/S004681771830282X?dgcid=raven_sd_via_email
https://link.springer.com/article/10.1245/s10434-018-7064-7
https://www.nature.com/articles/s41379-018-0110-y
https://www.sciencedirect.com/science/article/pii/S0046817718304350
https://www.sciencedirect.com/science/article/pii/S0046817718303009
https://onlinelibrary.wiley.com/doi/abs/10.1111/cyt.12662
https://onlinelibrary.wiley.com/doi/abs/10.1002/cncy.22073
https://www.sciencedirect.com/science/article/pii/S0039606018307402
December 2018Scientific Reports 8(1)
DOI: 10.1038/s41598-018-26526-x
http://clincancerres.aacrjournals.org/content/early/2018/12/11/1078-0432.CCR-18-1620
https://www.sciencedirect.com/science/article/pii/S0002944018305571
https://www.sciencedirect.com/science/article/pii/S0002944017311811
http://embor.embopress.org/content/early/2018/12/06/embr.201846556
December 2018Scientific Reports 8(1)
DOI: 10.1038/s41598-018-25669-1
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219964/
https://www.hindawi.com/journals/bmri/2018/7169595/
https://www.sciencedirect.com/science/article/pii/S0002944018308551
https://hccpjournal.biomedcentral.com/articles/10.1186/s13053-018-0100-6
https://www.sciencedirect.com/science/article/pii/S1877782118305101
http://www.scielo.br/scielo.php?pid=S0004-28032018002300230&script=sci_arttext
https://www.nature.com/articles/s41395-018-0414-z
https://www.sciencedirect.com/science/article/pii/S0002944018302062
https://www.sciencedirect.com/science/article/pii/S0002944018302529
http://ascopubs.org/doi/abs/10.1200/JCO.2019.37.4_suppl.267
https://link.springer.com/article/10.1245/s10434-019-07252-8
https://link.springer.com/article/10.1007/s00535-019-01570-0
Hear Pancreatic Cancer Stem Cells ROR
https://www.sciencedirect.com/science/article/pii/S0092867419303885
Syndecan 1 is a critical mediator of macropinocytosis in pancreatic cancer
https://www.nature.com/articles/s41586-019-1062-1
A Multiscale Map of the Stem Cell State in Pancreatic Adenocarcinoma
https://www.sciencedirect.com/science/article/pii/S0092867419302727
The Genetic Basis of Transcriptional and Spatial Heterogeneity of Squamous Features in Pancreatic Ductal Adenocarcinoma
Cellular Senescence, Represented by Expression of Caveolin-1, in Cancer-Associated Fibroblasts Promotes Tumor Invasion in Pancreatic Cancer.
https://www.ncbi.nlm.nih.gov/pubmed/30805811
A novel online prognostic tool to predict long‐term survival after liver resection for intrahepatic cholangiocarcinoma: The “metro‐ticket” paradigm
https://onlinelibrary.wiley.com/doi/abs/10.1002/jso.25480
Intracholecystic papillary-tubular neoplasms of the gallbladder – A clinicopathological study of 36 cases
https://www.sciencedirect.com/science/article/pii/S1092913419300577
IL‐33 overexpression in gallbladder cancers associated with pancreatobiliary maljunction
https://onlinelibrary.wiley.com/doi/abs/10.1111/his.13863
Staging gallbladder cancer with lymphadenectomy: the practical application of new AHPBA and AJCC guidelines
https://www.sciencedirect.com/science/article/abs/pii/S1365182X19304988
Prognostic Impact of Lymph Node Excision in T1 and T2 Gallbladder Cancer: a Population-Based and Propensity Score-Matched SEER Analysis
https://link.springer.com/article/10.1007/s11605-019-04175-3
Can we predict recurrence in WHO G1-G2 pancreatic neuroendocrine neoplasms? Results from a multi-institutional Spanish study.
https://www.ncbi.nlm.nih.gov/pubmed/30683515
Integrating next-generation sequencing to endoscopic retrograde cholangiopancreatography (ERCP)-obtained biliary specimens improves the detection and management of patients with malignant bile duct strictures
https://gut.bmj.com/content/early/2019/04/10/gutjnl-2018-317817.abstract
Distribution of dysplasia and cancer in the gallbladder: an analysis from a high cancer-risk population.
https://www.ncbi.nlm.nih.gov/pubmed/30036595
Dysplasia in Gallbladder: What Should We Do?
https://www.ncbi.nlm.nih.gov/pubmed/30215198
Systematic Selective Sampling of Cholecystectomy Specimens is Adequate to Detect Incidental Gallbladder Adenocarcinoma.
https://www.ncbi.nlm.nih.gov/pubmed/?term=31464710
The Pancreas as a Site of Metastasis or Second Primary in Patients with Small Bowel Neuroendocrine Tumors
https://link.springer.com/article/10.1245/s10434-019-07370-3
Staging for Ampullary Carcinoma: Is Less Actually More?
The Prognostic Relevance of the New 8th Edition of the Union for International Cancer Control Classification of TNM Staging for Ampulla of Vater Carcinoma
Role of Immunohistochemistry in the Subtyping of Periampullary Adenocarcinoma
https://journals.sagepub.com/doi/abs/10.1177/1066896919837606
Clinical relevance of pancreatobiliary and intestinal subtypes of ampullary and duodenal adenocarcinoma: Pattern of recurrence, chemotherapy, and survival after pancreatoduodenectomy.
https://www.ncbi.nlm.nih.gov/pubmed/30713128
Fear stress enhanced xenograft pancreatic tumor growth through activating epithelial-mesenchymal transition.
https://www.ncbi.nlm.nih.gov/pubmed/30733163
Wnt/β-catenin signalling plays diverse functions during the process of fibrotic remodelling in the exocrine pancreas.
https://www.ncbi.nlm.nih.gov/pubmed/30792046
Activation of IGF/IGF-IR signaling pathway fails to induce epithelial-mesenchymal transition in pancreatic cancer cells.
https://www.ncbi.nlm.nih.gov/pubmed/30799278
Cystic pancreatic neuroendocrine tumors: A more favorable lesion?
https://www.ncbi.nlm.nih.gov/pubmed/30704851
Evolution of surgical management of gallbladder carcinoma and impact on outcome: results from two decades at a single-institution
https://www.sciencedirect.com/science/article/abs/pii/S1365182X19304964
Should we regard all main duct type intraductal papillary mucinous neoplasms of the pancreas (MD-IPMN) as an indication of surgery? -A retrospective study in 29 patients with MD-IPMN showing mural nodules.
https://www.ncbi.nlm.nih.gov/pubmed/30679137
Acute Recurrent and Chronic Pancreatitis as Initial Manifestations of Cystic Fibrosis and Cystic Fibrosis Transmembrane Conductance Regulator-Related Disorders.
https://www.ncbi.nlm.nih.gov/pubmed/31268981
The Surveillance Patterns of Incidentally Detected Pancreatic Cysts Vary Widely and Infrequently Adhere to Guidelines.
https://www.ncbi.nlm.nih.gov/pubmed/31268984
Oncogenic KRAS Reduces Expression of FGF21 in Acinar Cells to Promote Pancreatic Tumorigenesis in Mice on a High-Fat Diet.
https://www.ncbi.nlm.nih.gov/pubmed/31352001
Silibinin inhibited autophagy and mitochondrial apoptosis in pancreatic carcinoma by activating JNK/SAPK signaling.
https://www.ncbi.nlm.nih.gov/pubmed/31351801
Impact of Changes in the American Joint Committee on Cancer Staging Manual, Eighth Edition, for Pancreatic Ductal Adenocarcinoma.
https://www.ncbi.nlm.nih.gov/pubmed/31268985
Incidental Splenic Findings in Pancreatosplenectomy Specimens Resected for Primary Pancreatic Lesions.
https://www.ncbi.nlm.nih.gov/pubmed/31269535
Well-differentiated Pancreatic Neuroendocrine Tumor in a Patient With Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM).
https://www.ncbi.nlm.nih.gov/pubmed/31261289
The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy.
https://www.ncbi.nlm.nih.gov/pubmed/31259422
miR-149-5p protects against high glucose-induced pancreatic beta cell apoptosis via targeting the BH3-only protein BIM.
https://www.ncbi.nlm.nih.gov/pubmed/31260649
Interaction of amyloidogenic proteins in pancreatic β cells from subjects with synucleinopathies.
https://www.ncbi.nlm.nih.gov/pubmed/29536165
Mutational profiling and immunohistochemical analysis of a surgical series of ampullary carcinomas.
https://www.ncbi.nlm.nih.gov/pubmed/31256008
Autoantibody-targeted TAAs in pancreatic cancer: A comprehensive analysis.
https://www.ncbi.nlm.nih.gov/pubmed/31255446
CT radiomics associations with genotype and stromal content in pancreatic ductal adenocarcinoma.
https://www.ncbi.nlm.nih.gov/pubmed/31243486
Alterations of the bile microbiome in primary sclerosing cholangitis.
https://www.ncbi.nlm.nih.gov/pubmed/31243055
Intraoperative Near-infrared Imaging Can Identify Neoplasms and Aid in Real-time Margin Assessment During Pancreatic Resection.
https://www.ncbi.nlm.nih.gov/pubmed/31188797
Characterization of spatial distribution of tumor-infiltrating CD8+ T cells refines their prognostic utility for pancreatic cancer survival.
https://www.ncbi.nlm.nih.gov/pubmed/31186528
Morphological classification of pancreatic ductal adenocarcinoma that predicts molecular subtypes and correlates with clinical outcome.
https://www.ncbi.nlm.nih.gov/pubmed/31201285
Does Neoadjuvant Chemotherapy Change the Role of Regional Lymphadenectomy in Pancreatic Cancer Survival?
https://www.ncbi.nlm.nih.gov/pubmed/31210664
OCIAD1 promoted pancreatic ductal adenocarcinoma migration by regulating ATM.
https://www.ncbi.nlm.nih.gov/pubmed/31221523
The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice.
https://www.ncbi.nlm.nih.gov/pubmed/31221853
Cytohistological diagnosis of pancreatic serous cystadenoma: a multimodal approach.
https://www.ncbi.nlm.nih.gov/pubmed/31235542
Genomic ERBB2/ERBB3 mutations promote PD-L1-mediated immune escape in gallbladder cancer: a whole-exome sequencing analysis.
https://www.ncbi.nlm.nih.gov/pubmed/29954840
Fasting and Glucose-Stimulated Changes in Plasma Glucagon in Pancreatic Cancer: Potential Biomarkers for Detection?
https://www.ncbi.nlm.nih.gov/pubmed/30531245
Spontaneous Regression of Metastatic Pancreatic Cancer: A Role for Recurrent Inflammation.
https://www.ncbi.nlm.nih.gov/pubmed/30531247
Risk Factors for Pancreatic Stone Formation in Type 1 Autoimmune Pancreatitis: A Long-term Japanese Multicenter Analysis of 624 Patients.
https://www.ncbi.nlm.nih.gov/pubmed/30540679
Pancreatic Cancer: A Rare Cause of Abdominal Pain in Severe Cystic Fibrosis.
https://www.ncbi.nlm.nih.gov/pubmed/30531246
Targeted next-generation sequencing identifies distinct clinicopathologic and molecular entities of intraductal papillary neoplasms of the bile duct.
https://www.ncbi.nlm.nih.gov/pubmed/31231124
Uniform and Robust Nuclear Expression of HES1 in Neuroendocrine Neoplasms.
https://www.ncbi.nlm.nih.gov/pubmed/31232134
SATB2 in Neuroendocrine Neoplasms: Strong Expression is Restricted to Well-Differentiated Tumors of Lower Gastrointestinal Tract Origin and is More Frequent in Merkel Cell Carcinoma among Poorly Differentiated Carcinomas.
https://www.ncbi.nlm.nih.gov/pubmed/31233624
Imbalance of Genes Encoding Natural Killer Immunoglobulin-Like Receptors and Human Leukocyte Antigen in Patients With Biliary Cancer.
https://www.ncbi.nlm.nih.gov/pubmed/31229495
IQGAP1 Maintains Pancreatic Ductal Adenocarcinoma Clonogenic Growth and Metastasis.
https://www.ncbi.nlm.nih.gov/pubmed/30540680
Tenascin C, Fibronectin, and Tumor-Stroma Ratio in Pancreatic Ductal Adenocarcinoma.
https://www.ncbi.nlm.nih.gov/pubmed/30451798
Is Routine Splenectomy Justified for All Left-Sided Pancreatic Cancers? Histological Reappraisal of Splenic Hilar Lymphadenectomy.
https://www.ncbi.nlm.nih.gov/pubmed/30607766
A case of high-grade pancreatic intraepithelial neoplasia concomitant with type 1 autoimmune pancreatitis: The process underlying both conditions.
https://www.ncbi.nlm.nih.gov/pubmed/30719801
Pseudomyxoma Peritonei After a Total Pancreatectomy for Intraductal Papillary Mucinous Neoplasm With Colloid Carcinoma in Lynch Syndrome.
https://www.ncbi.nlm.nih.gov/pubmed/30531244
Gastric Neuroendocrine Tumor and Duodenal Gastrinoma With Chronic Autoimmune Atrophic Gastritis.
https://www.ncbi.nlm.nih.gov/pubmed/30531243
The Molecular and Clinical Landscape of Pancreatic Neuroendocrine Tumors.
https://www.ncbi.nlm.nih.gov/pubmed/30531241
Emerging Evidence for the Clinical Relevance of Pancreatic Cancer Exosomes.
https://www.ncbi.nlm.nih.gov/pubmed/30531240
Dietary Fiber and the Risk of Pancreatic Cancer.
https://www.ncbi.nlm.nih.gov/pubmed/30489447
Proinsulin Expressing Neuroendocrine Tumors of the Pancreas: An Underrecognized Entity.
https://www.ncbi.nlm.nih.gov/pubmed/30451800
Perineural Invasion is a Strong Prognostic Moderator in Ampulla of Vater Carcinoma: A Meta-analysis.
https://www.ncbi.nlm.nih.gov/pubmed/30451797
Expression of Epithelial-Mesenchymal Transition Proteins in Pancreatic Anaplastic (Undifferentiated) Carcinoma.
https://www.ncbi.nlm.nih.gov/pubmed/30451796
Pancreatic Lipomatous Hamartoma: A Hitherto Unrecognized Variant.
https://www.ncbi.nlm.nih.gov/pubmed/29738363
Intraobserver and Interobserver Variability in the Assessment of Dysplasia in Ampullary Mucosal Biopsies.
https://www.ncbi.nlm.nih.gov/pubmed/29738360
Serous Neoplasms of the Pancreas: A Comprehensive Review.
https://www.ncbi.nlm.nih.gov/pubmed/30141993
Factors Impacting the Performance Characteristics of Bile Duct Brushings: A Clinico-Cytopathologic Analysis of 253 Patients.
https://www.ncbi.nlm.nih.gov/pubmed/29582676
Total Serum Cholesterol and Pancreatic Cancer Risk: What Is the Link?
https://www.ncbi.nlm.nih.gov/pubmed/31254172
Cytopathology of anaplastic carcinoma of the pancreas: Review of a rare entity and description of a variant with signet ring cell features.
https://www.ncbi.nlm.nih.gov/pubmed/31254330
Next generation sequencing of endoscopic ultrasound guided microbiopsies from pancreatic cystic neoplasms.
https://www.ncbi.nlm.nih.gov/pubmed/31278869
Management of solid pseudopapillary neoplasms of pancreas: A single center experience of 243 consecutive patients.
https://www.ncbi.nlm.nih.gov/pubmed/31281058
Immune cell score in pancreatic cancer-comparison of hotspot and whole-section techniques.
https://www.ncbi.nlm.nih.gov/pubmed/30843106
Surgical treatment of metastatic pancreatic ductal adenocarcinoma: A review of current literature. - PubMed - NCBI
https://www.ncbi.nlm.nih.gov/pubmed/31285145
Histomorphology of pancreatic cancer in patients with inherited ATM serine/threonine kinase pathogenic variants. - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/31285527
Adjuvant Therapy for Ampullary Cancer | Oncology | JAMA Surgery | JAMA Network
https://jamanetwork.com/journals/jamasurgery/article-abstract/2734846
Squamous cell carcinoma of the common bile duct: A case report with genomic profiling. - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/31286611
Overexpression of folate receptor alpha is an independent prognostic factor for outcomes of pancreatic cancer patients. - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/29926190
Comparison of Monitor-Image and Printout-Image Methods in Ki-67 Scoring of Gastroenteropancreatic Neuroendocrine Tumors. - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/30367334
Neuroendocrine Liver Metastasis-a Specific Set of Markers to Detect Primary Tumor Sites. - PubMed - NCBI
https://www.ncbi.nlm.nih.gov/pubmed/30456697
In Situ Hybridization Analysis of Long Non-coding RNAs MALAT1 and HOTAIR in Gastroenteropancreatic Neuroendocrine Neoplasms. - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/30600442
Trends in biomarker discoveries for the early detection and risk stratification of pancreatic cancer using omics studies. - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/31298060
Development of the Intrahepatic and Extrahepatic Biliary Tract: A Framework for Understanding Congenital Diseases. - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/31299162
Loss of Setd2 promotes Kras-induced acinar-to-ductal metaplasia and epithelia-mesenchymal transition during pancreatic carcinogenesis. - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/31300513
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The Relationship of Acute Pancreatitis and Pancreatic Cancer. - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/31306306
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A Novel Approach: Local Resection for Ampullary GIST-Case Report and Review of Literature. - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/27251298
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Immune cell score in pancreatic cancer-comparison of hotspot and whole-section techniques. - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/30843106
Alkalin phosphatase is a predictive factor of unresecability in ampullary and periampullary tumors. - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/29492936
Laterally Spreading Adenocarcinoma Involving the Lower Bile Duct and Duodenum Expressing Heterogeneous Immunohistochemical Phenotypes. - PubMed - NCBI
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Is there any relationship between clinical parameters and histopathologic features of gallbladder specimens obtained from living liver donors? - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/31293268
Prospective multi-center study of surgeon’s assessment of the gallbladder compared to histopathological examination to detect incidental malignancy. - PubMed - NCBI
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Compromising Patient Care: Gross Payment Disparities in Dermatopathology-Part II. - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/29282184
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Vasohibin-2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma. - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/31074083
Lipase hypersecretion syndrome: A distinct form of paraneoplastic syndrome specific to pancreatic acinar carcinomas. - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/31300257
Intraobserver and Interobserver Variability in the Assessment of Dysplasia in Ampullary Mucosal Biopsies. - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/29738360
Challenges in the management of adenocarcinoma of ampulla of Vater in pregnancy: A case report and review of literature. - PubMed - NCBI
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Gallbladder adenocarcinoma diagnosed from cutaneous metastases occurring along the tract of a ventriculoperitoneal shunt. - PubMed - NCBI
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Statin Use and Risk of Pancreatic Cancer: An Updated Meta-analysis of 26 Studies. - PubMed - NCBI
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Tissue curvature and apicobasal mechanical tension imbalance instruct cancer morphogenesis. - PubMed - NCBI
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Chromatin remodelling controls pancreatic tissue fate. - PubMed - NCBI
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The hepatic pre-metastatic niche in pancreatic ductal adenocarcinoma. - PubMed - NCBI
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Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/31157963
Rosai-Dorfman Disease of the Pancreas Shows Significant Histologic Overlap With IgG4-related Disease. - PubMed - NCBI
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Validity and usefulness of a single-item measure of patient-reported bother from side effects of cancer therapy. - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/29131323
Genetic Analysis of Brazilian Patients with Gallbladder Cancer. - PubMed - NCBI
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NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls. - PubMed - NCBI
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Clinicopathological and immunological features of follicular pancreatitis - a distinct disease entity characterised by Th17 activation. - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/30515871
Increase of Tumor Infiltrating γδ T-cells in Pancreatic Ductal Adenocarcinoma Through Remodeling of the Extracellular Matrix by a Hyaluronan Synthe… - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/30589828
Global Patterns and Trends in Pancreatic Cancer Incidence: Age, Period, and Birth Cohort Analysis. - PubMed - NCBI
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Comparative Accuracy of Tumor Size Assessment and Stage Analysis by Imaging Modalities Versus Gross Examination for Pancreatic Ductal Adenocarcinoma. - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/30629023
Microvessel Density and Impact of Angiogenesis on Survival of Resected Pancreatic Cancer Patients: A Systematic Review and Meta-analysis. - PubMed - NCBI
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Wolfram syndrome: A rare case report. - PubMed - NCBI
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Comparative study of lung and extrapulmonary poorly differentiated neuroendocrine carcinomas: A SEER database analysis of 162,983 cases. - PubMed - NCBI
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RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer. - PubMed - NCBI
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KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism. - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/30423298
Advances in the cytologic diagnosis of gastroenteropancreatic neuroendocrine neoplasms. - PubMed - NCBI
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African American women with gum disease and tooth loss face higher pancreatic cancer risk. - PubMed - NCBI
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Cytology with rapid on-site examination (ROSE) does not improve diagnostic yield of EUS-FNA of pancreatic cystic lesions. - PubMed - NCBI
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New Nodal Staging for Primary Pancreatic Neuroendocrine Tumors: A Multi-institutional and National Data Analysis. - PubMed - NCBI
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Age-related morphological changes in the pancreas and their association with pancreatic carcinogenesis. - PubMed - NCBI
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Patterns, Timing, and Predictors of Recurrence Following Pancreatectomy for Pancreatic Ductal Adenocarcinoma. - PubMed - NCBI
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Extracellular matrix proteins and carcinoembryonic antigen-related cell adhesion molecules characterize pancreatic duct fluid exosomes in patients … - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/29339034
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SWI/SNF component ARID1A restrains pancreatic neoplasia formation. - PubMed - NCBI
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Lysine methyltransferase 2D regulates pancreatic carcinogenesis through metabolic reprogramming. - PubMed - NCBI
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Macrophage-derived exosomal microRNA-501-3p promotes progression of pancreatic ductal adenocarcinoma through the TGFBR3-mediated TGF-β signaling pa… - PubMed - NCBI
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Management and surveillance of non-functional pancreatic neuroendocrine tumours: Retrospective review. - PubMed - NCBI
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Whole-exome sequencing of duodenal neuroendocrine tumors in patients with neurofibromatosis type 1. - PubMed - NCBI
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Cytological features of hepatoid adenocarcinoma of the gallbladder: A case report with immunocytochemical analyzes. - PubMed - NCBI
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Mobilization of CD8+ T Cells via CXCR4 Blockade Facilitates PD-1 Checkpoint Therapy in Human Pancreatic Cancer. - PubMed - NCBI
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Pyloric Gland Adenoma (PGA) of the Gallbladder: A Unique and Distinct Tumor from PGAs of the Stomach, Duodenum, and Pancreas. - PubMed - NCBI
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Detection of NRG1 Gene Fusions in Solid Tumors. - PubMed - NCBI
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NRG1 Gene Fusions Are Recurrent, Clinically Actionable Gene Rearrangements in KRAS Wild-Type Pancreatic Ductal Adenocarcinoma. - PubMed - NCBI
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Design of an immunohistochemistry biomarker panel for diagnosis of pancreatic adenocarcinoma. - PubMed - NCBI
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The Prognosis Value of PIWIL1 and PIWIL2 Expression in Pancreatic Cancer. - PubMed - NCBI
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Primary pancreatic diffuse large B-cell lymphoma diagnosed by endoscopic ultrasound guided FNAC: A rare entity. - PubMed - NCBI
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The Histone Demethylase KDM3A, Increased in Human Pancreatic Tumors, Regulates Expression of DCLK1 in and Promotes Tumorigenesis in Mice. - PubMed - NCBI
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The diagnostic and cellularity yield of reverse bevel versus fork-tip fine needle biopsy. - PubMed - NCBI
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Prolactin promotes fibrosis and pancreatic cancer progression. - PubMed - NCBI
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Management of MEN1 Related Nonfunctioning Pancreatic NETs: A Shifting Paradigm: Results From the DutchMEN1 Study Group. - PubMed - NCBI
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A New Scoring System to Predict Recurrent Disease in Grade 1 and 2 Nonfunctional Pancreatic Neuroendocrine Tumors. - PubMed - NCBI
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Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes. - PubMed - NCBI
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High-Mobility Group Box 1 expression predicts survival of patients after resection of adenocarcinoma of the ampulla of Vater. - PubMed - NCBI
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ARF6 and AMAP1 are major targets of KRAS and TP53 mutations to promote invasion, PD-L1 dynamics, and immune evasion of pancreatic cancer. - PubMed - NCBI
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Analysis of microRNA expression in brush cytology specimens improves the diagnosis of pancreatobiliary cancer. - PubMed - NCBI
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Relationship between Helicobacter pylori-positivity in the gallbladder and stomach and effect on gallbladder pathologies. - PubMed - NCBI
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Does Surgical Margin Impact Recurrence in Noninvasive Intraductal Papillary Mucinous Neoplasms?: A Multi-institutional Study. - PubMed - NCBI
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Circulating Tumor Cells Dynamics in Pancreatic Adenocarcinoma Correlate With Disease Status: Results of the Prospective CLUSTER Study. - PubMed - NCBI
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DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth. - PubMed - NCBI
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Impact of tumour budding grade in 310 patients who underwent surgical resection for extrahepatic cholangiocarcinoma. - PubMed - NCBI
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Expression of Monocarboxylate Transporter 1 Is Associated With Better Prognosis and Reduced Nodal Metastasis in Pancreatic Ductal Adenocarcinoma. - PubMed - NCBI
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Time to Adjuvant Systemic Therapy Following Pancreatic Cancer Resection and Effect on Outcome. - PubMed - NCBI
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Association Between Pancreatic Cystic Lesions and High-grade Intraepithelial Neoplasia and Aging: An Autopsy Study. - PubMed - NCBI
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Detection of Reg3γ by Immunohistochemistry in Cerulein-Induced Model of Acute Pancreatic Injury in Mice and Rats. - PubMed - NCBI
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Inflammation Promotes Progression of Pancreatic Cancer Through WNT/β-Catenin Pathway-Dependent Manner. - PubMed - NCBI
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Evaluation of a biomarker for the diagnosis of pancreas cancer using an animal model. - PubMed - NCBI
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Dissecting the presence of malignant squamous cells in pancreatic cytopathology: A case series. - PubMed - NCBI
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Mouse pancreatic ductal organoid culture as a relevant model to study exocrine pancreatic ion secretion. - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/31409889
Lipid droplet velocity is a microenvironmental sensor of aggressive tumors regulated by V-ATPase and PEDF. - PubMed - NCBI
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Grading Pancreatic Neuroendocrine Tumors by Ki-67 Index Evaluated on Fine-Needle Aspiration Cell Block Material. - PubMed - NCBI
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Metastatic low-grade endometrial stromal sarcoma of uterus presenting as a primary pancreatic tumor: case presentation and literature review. - PubMed - NCBI
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First-in-human Study of Mivebresib (ABBV-075), an Oral Pan-inhibitor of Bromodomain and Extra Terminal Proteins, in Patients with Relapsed/Refracto… - PubMed - NCBI
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Significance of Examined Lymph Node Number in Accurate Staging and Long-term Survival in Resected Stage I-II Pancreatic Cancer-More is Better? A La… - PubMed - NCBI
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Molecular envoys pave the way for pancreatic cancer to invade the liver. - PubMed - NCBI
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Cellular Senescence, Represented by Expression of Caveolin-1, in Cancer-Associated Fibroblasts Promotes Tumor Invasion in Pancreatic Cancer. - PubMed - NCBI
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Coexisting pancreatic serous cystadenoma and pancreatic ductal adenocarcinoma: A cytological-pathologic correlation with literature review. - PubMed - NCBI
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